Synthesis of 2- and 2,3-substituted Pyrazolo[1,5- a ]pyridines: Scope and mechanistic considerations of a domino direct alkynylation and cyclization of n -iminopyridinium ylides using alkenyl bromides, alkenyl iodides, and alkynes

Article abstract of DOI:10.1021/jo201303x

Direct functionalization and tandem processes have both received considerable recent interest due to their cost and time efficiency. Herein we report the synthesis of difficult to obtain 2-substituted pyrazolo[1,5-a] pyridines through a tandem palladium-catalyzed/silver-mediated elimination/direct functionalization/cyclization reaction involving N-benzoyliminopyridinium ylides. As such, these biologically important molecules are prepared in an efficient, high-yielding manner, only requiring a two-step sequence from pyridine. Aryl-substituted alkenyl bromides and iodides are effective ylide coupling partners. Mechanistic studies led to the use of terminal alkynes, which extended the scope of the reaction to include alkyl substitution on the unsaturated reactive site. The optimization, scope, and mechanistic considerations of the process are discussed.

Full text of DOI:10.1021/jo201303x

ARTICLE
pubs.acs.org/joc
Synthesis of 2- and 2,3-Substituted Pyrazolo[1,5-a]pyridines: Scope
and Mechanistic Considerations of a Domino Direct Alkynylation and
Cyclization of N-Iminopyridinium Ylides Using Alkenyl Bromides,
Alkenyl Iodides, and Alkynes
James J. Mousseau, James A. Bull, Carolyn L. Ladd, Angꢀelique Fortier, Daniela Sustac Roman, and
Andrꢀe B. Charette*
Department of Chemistry, Universitꢀe de Montrꢀeal, P.O. Box 6128, Station Downtown, Montrꢀeal, Quꢀebec, Canada H3C 3J7
S Supporting Information
b
ABSTRACT: Direct functionalization and tandem processes have
both received considerable recent interest due to their cost and time
efficiency. Herein we report the synthesis of difficult to obtain
2-substituted pyrazolo[1,5-a]pyridines through a tandem palladium-
catalyzed/silver-mediated elimination/direct functionalization/cycli-
zation reaction involving N-benzoyliminopyridinium ylides. As such,
these biologically important molecules are prepared in an efficient,
high-yielding manner, only requiring a two-step sequence from pyridine. Aryl-substituted alkenyl bromides and iodides are effective
ylide coupling partners. Mechanistic studies led to the use of terminal alkynes, which extended the scope of the reaction to include
alkyl substitution on the unsaturated reactive site. The optimization, scope, and mechanistic considerations of the process are
discussed.
’ INTRODUCTION
involves a [3 + 2] cycloaddition of a dipolarophile bearing an
electron-withdrawing group onto an N-aminopyridinium salt
(Scheme 1).5 Typically, 2,3-disubstituted or 3-substituted pyr-
azolopyridines are obtained in moderate yields. Pyrazolopyri-
dines bearing 2-substituents may be accesed via various intramolecular
cyclizations, including displacements,6 radical additions,7 nitrene
insertions,8 and through rearrangements of pyridine derivatives
bearing aziridine groups (Scheme 1).5b,9 Several of these trans-
formations are high yielding but require several synthetic steps
for the synthesis of the reactive precursors, hampering the efficiency
of the sequence.
Modern synthetic methodology often aims to emphasize
molecular complexity while minimizing the number of synthetic
steps required to achieve this. Processes whereby several bonds
are made/broken in a single reaction vessel have garnered much
attention.10 These domino sequences are often atom economical
and save considerable resources in both time and cost by reducing
the number of operations required to reach a specific target.
Concomitantly, the direct introduction of functionality via the
functionalization of CÀH bonds is a highly attractive synthetic
strategy.11 These processes are an opportunistic new class of
CÀC bond forming reactions, due in part to the ubiquity of
CÀH bonds in Nature. Consequently, these reactions have
emerged as viable, efficient, and more environmentally friendly
alternatives to classical cross-coupling reactions.12 Combining
Nitrogen-containing heterocycles are key components in a
myriad of biologically active compounds.1 Indeed, recent surveys
have reported that greater than 90% of molecules currently under
investigation by pharmaceutical companies contain nitrogen
heterocycles, and of these, pyridine and pyridine derivatives
constitute the most important family of compounds.2 As such,
there has been significant interest in developing efficient meth-
ods for the synthesis of these molecular architectures.
Pyrazolopyridines constitute an important class of pharmaco-
logically active compounds and are often employed as indole
isosteres due to their relatively high metabolic stability.3 Notably,
pyrazolo[1,5-a]pyridines (Figure 1), specifically when substi-
tuted in the 2-position, are known for their ability to act as
dopamine D3 agonists and antagonists and are used in the treatment
of psycho-stimulant addictions. Additionally the D3 receptor
controls dopamine synthesis, release, and neuronal firing and is
linked to the pathophysiology of Parkinson’s disease as well as
schizophrenia.3 Other applications of pyrazolo[1,5-a]pyridines
include an adenosine A1 receptor antagonist with potent diuretic
activity as well as their use in the treatment of cardiac arrhythmias
and for the diagnosis of ischemic heart diseases.4 Finally, certain
pyrazolo[1,5-a]pyridine derivatives have also been found to have
superior reactivity than acyclovir and its prodrug valacyclovir as
antiherpetic agents.4
Despite their clear importance, the synthesis of 2-substituted
pyrazolo[1,5-a]pyridines (generalized as pyrazolopyridines) re-
mains a challenge. The most common method for their preparation
Received: July 6, 2011
Published: September 08, 2011
r
2011 American Chemical Society
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Figure 1. Various biologically active pyrazolo[1,5-a]pyridines.
Scheme 1. Previous Reported Methods for the Preparation
of 2-Substituted Pyrazolo[1,5-a]pyridines
Scheme 2. Synthesis of Pyridine Derivatives and Direct
Functionalization Reactions Employing N-Iminopyridinium
Ylides
CÀH activation with subsequent tandem reactions presents a
highly desirable approach to molecular synthesis.
results toward a divergent synthesis of pyrazolo[1,5-a]pyridines
from N-iminopyridinium ylides and alkenyl iodides under palla-
dium catalysis.16 Herein we disclose further application of this
transformation, expanding the scope of the alkenyl iodides, and
we report the application of alkenyl bromides. Studies into the
mechanism of the reaction are disclosed which suggest that alkynes
are the true substrates, formed under the coupling conditions. The
useofalkynesastheinitialsubstratefurtherdiversified the breadth of
potential coupling partners. The scope of the reaction using alkynyl
coupling partners is also explored. The process constitutes a direct
alkynylation reaction in tandem with intramolecular ring closing to
generate 2-substituted pyrazolo[1,5-a]pyridines in two steps from
pyridine in good to excellent yields.
Recent examples of direct reactions on activated pyridines to
generate 2-substituted pyridine and pyridine derivatives have
clearly demonstrated the effectiveness of CÀH derivatization
over traditional cross-coupling methods, especially over using
2-metallopyridines in cross-coupling processes.13 Our research
program has been focused in developing novel methodologies
aimed toward the preparation of various pyridine derivatives
from N-iminopyridinium ylides (Scheme 2).14 As part of this
mandate we have recently demonstrated that N-iminopyridi-
nium ylides are versatile substrates for both palladium- and
copper-catalyzed direct functionalization reactions.14dÀf These
include both the direct and benzylic arylation of these ylides as
well as a direct alkenylation reaction. N-Benzoyliminopyridinium
ylide 1 is readily available on large scale in excellent yield through
a one-pot amination/benzoylation of pyridine using O-(2,4-
dinitrophenyl)hydroxylamine.15 We recently disclosed preliminary
’ RESULTS AND DISCUSSION
Reaction Optimization. Pyrazolopyridine 4a was first ob-
served during the optimization of our previously reported direct
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Scheme 3. Effect of Altering the Base in the Direct Alkenylation Reaction
Table 1. Selected Screening of Silver Salts
Table 2. Selected Screening of Palladium and Ligand Sources
entrya
silver source
yieldb (%)
entrya
palladium
ligand
P(t-Bu)3
yieldb (%)
1À5
AgOTf, AgSbF4, AgBF4, AgPF6, Ag2SO4
<5 (<5)c
<5 (16)c
13 (21)c
45 (50)c
51 (51)c
1
2
Pd(dba)2
Pd(TFA)2
PdI 2
31
40
46
52
55
50
54
59
60
61
62
63
6
7
8
9
AgTFA
AgOAc
Ag2CO3
AgOBz
P(t-Bu)3
3
P(t-Bu)3
4
Pd(OAc)2
PdBr2
P(t-Bu)3
5
P(t-Bu)3
a 1.5 equiv of 1a and 1 equiv of 2a were used. b 1H NMR yield
determined using 1,3,5-trimethoxybenzene as an internal standard.
c Number in parentheses indicates the yield observed with the inclusion
of 2 equiv of K2CO3.
6
PdBr2
P(Cy)3
7
PdBr2
P(2,4,6-MeOPh)3
PPh3
8
PdBr2
9
PdBr2
P(2-MePh)3
BINAP
10
11
12
PdBr2
alkenylation reaction (Scheme 3). Reacting ylide 1a with (E)-(2-
iodovinyl)benzene (2a) in the presence of Pd(OAc)2 (5 mol %),
P(t-Bu)3 (15 mol %), and K2CO3 (3 equiv) gave the 2-alkeny-
lated pyridinium 3 in moderate 50% yield. However, varying the
base to Ag2CO3 (3 equiv) gave the 2-substituted pyrazolopyr-
idine 4a in 45% isolated yield along with an equal amount of
benzoic acid.
PdBr2
P(n-Bu)3
PdBr2
P(4-MeOPh)3
a 1.5 equiv of 1a and 1 equiv of 2a were used. b 1H NMR yield
determined using 1,3,5-trimethoxybenzene as an internal standard.
the yield (entry 9). Varying the quantity of silver was deleter-
ious, with the optimal loading being 3 equiv.
Cognizant of the difficulties in preparing 2-substituted
pyrazolopyridines, we proceeded to optimize the reaction
conditions to furnish 4a. The source of silver proved to be
critical for the transformation to proceed (Table 1). Most
silver reagents were incompatible for the reaction, even upon
the inclusion of an additional external base (entries 1À5).
Given the elegant work of Fagnou and Echavarren, while
considering that a direct CÀH functionalization may be a key
step in the process, it was thought that the inclusion of an
acetate/carbonate motif may be essential to promote a con-
certed metalation/deprotonation (CMD) of the pyridinium
ylide.17 Gratifyingly, AgTFA (entry 6), AgOAc (entry 7), and
Ag2CO3 (entry 8) gave the product in increasing yields,
indeed demonstrating the importance of this moiety in the
transformation. In most cases, the inclusion of an ancillary
carbonate source led to modest improvement in yields. Silver
benzoate was determined to be the most favorable, in which
case the introduction of an external base was not beneficial to
We next considered the palladium/ligand catalytic system
(Table 2). All palladium sources examined promoted the reac-
tion (entries 1À4); however, PdBr2 offered the highest yield
(entry 5). The reaction was remarkably insensitive to the ligand
employed witharangeofinexpensivephosphinereagentsproviding
comparable levels of conversion to the desired heterocycle, display-
ing a high degree of versatility with regards to choice of cocatalyst
(entries 5À12). However, P(4-MeOPh)3 did give slightly im-
proved results (entry 12) and thus was chosen for the remaining
optimization. A ligand-to-palladium ratio of 3:1 provided the best
results. It is noteworthy that palladium/ligand complexes such as
Pd(i-Mes)-napquin dimer, (PPh3)2Pd(OAc)2, and PEPPSI were
also operative, albeit with lower yields.
The reaction was successful in all solvents examined (Table 3).
Several polar, aromatic, and ethereal solvents were very well tolerated,
further displaying a lack of reaction component sensitivity (entries
3À9). Though dimethoxyethane was found to give the best yield, 1,4-
dioxane was ultimately chosen due to its lower volatility (entry 8).
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Table 3. Selected Reaction Solvent Screening
Table 4. Selected Optimization of Reaction Conditions:
Concentration, Stoichiometry, Temperature
entrya
solvent
yieldb (%)
entry
conc (M)
ylide/iodide
temp (°C)
yielda (%)
1
2
3
4
5
6
7
8
9
dichloroethane
N,N-dimethylformamide
chlorobenzene
acetonitrile
28
46
54
62
63
64
68
69
71
1
2
0.2
0.2
0.2
0.2
0.2
0.1
0.4
0.8
0.2
0.2
0.2
0.2
0.2
0.75/1.0
1.0/1.0
1.5/1.0
2.0/1.0
4.0/1.0
2.0/1.0
2.0/1.0
2.0/1.0
2.0/1.0
2.0/1.0
2.0/1.0
2.0/1.0
2.0/1.0
125
125
125
125
125
125
125
125
95
60
63
3
74
toluene
4
80
tetrahydrofuran
N-methylpyrrolidinone
1,4-dioxane
5
84
6
64
7
70
dimethoxyethane
8
55
a 1.5 equiv of 1a and 1 equiv of 2a were used. b 1H NMR yield
9
40
determined using 1,3,5-trimethoxybenzene as an internal standard.
10
11
12
13
100
110
125
135
62
68
80 (78)b
Among the final variables to be considered were the concen-
tration of the reagents along with the reaction temperature and
time (Table 4). The reaction performed better when an excess of
the ylide relative to the iodide coupling partner was employed
(entries 1À5). Using 2 equiv of the ylide increased the yield to
80% (entry 4). Further increasing the excess to 4 equiv provided
only a marginal improvement (84%, entry 5), which did not
justify the large excess. The optimal concentration was 0.2 M
with respect to the iodide (entries 5À8). Reactivity was noted at
temperatures as low as 95 °C (40% yield, entry 9), and a
temperature of 125 °C provided the best results. It is interesting
to note that increasing the temperature above this point gave
poorer results (entry 13) because of the increase in degradation
products. The time of the reaction was also considered, and 16 h
was found to be necessary for increased levels of conversion.
As a result, the optimal conditions for the tandem direct
functionalization/cyclization reaction involved 1 equiv of the
alkenyl iodide 2a, 2 equiv of the pyridinium ylide 1a, 3 equiv of
AgOBz, 5 mol % of PdBr2, 15 mol % of P(4-MeOPh)3, 0.2 M in
1,4-dioxane at 125 °C, providing the pyrazolopyridine 4a in 78%
isolated yield.
Reaction Scope: Alkenyl Halides. With an optimized set of
conditions in hand, we were keen to investigate the scope of the
reaction. We previously reported a convenient, high-yielding, and
highly stereoselective method for the preparation of β-aryl vinyl
halides using the anions of dihalomethanes.18 With access to a
wide range of functionalized styryl halides we first employed
these reagents to challenge the current methodology.
The use of both E- and Z-β-styryl iodide successfully formed
2-phenylpyrazolopyridine 4a (Table 5, entries 1 and 2), though
the E-isomer afforded a higher yield. Styryl bromides were viable
reacting partners, extending the breadth of potential pseudo-
electrophile coupling partners. Interestingly, both β- and α-styryl
bromide (2c and 2d) furnished the same pyrazolopyridine product
with the phenyl ring at the 2-position (entries 3 and 4).
Unfortunately, styryl chlorides were inoperative (entry 5),
presumably due to the inability of the reagent to undergo
oxidative addition under the reaction conditions.19 Pleasingly,
using 0.5 equiv of bis-vinyl iodide 2f gave the corresponding
69
a 1H NMR yield determined using 1,3,5-trimethoxybenzene as an
internal standard. b Isolated yield.
bis-pyrazolopyridine 4b in 40% yield under unmodified con-
ditions (entry 6). Electron-neutral substitution on the aro-
matic ring of the halide had little effect on the reaction
(entries 7À10). Naphthyl as well as tolyl vinyl halides gave
the desired products in moderate to good yield (entries
7À10). The presence of an o-methyl group gave only a slight
decrease in yield, demonstrating little sensitivity toward steric
hindrance. Electron-donating groups at the 2-, 3-, and 4-posi-
tions of the phenyl ring afforded the corresponding pyrazo-
lopyridines in moderate to very good yield, with the (E)-β-
aryl vinyl iodide bearing a benzyl ether proving to be the most
reactive (entries 11À14). Concurrently we assessed electron-
poor substrates (entries 15À18), and comparable yields were
observed for arenes bearing nitrile and fluorine functionality.
Styryl iodides bearing bromides or chlorides on the aryl
component reacted in an extremely chemoselective fashion
with no arylated byproduct observed (entries 18À21). These
provide attractive scaffolds for further elaboration via cross-
coupling reactions. However, substrates with aryl iodides
provided complex mixtures of products.
We next varied the type of vinyl halide aiming to introduce
vinyl or alkyl substituents onto the pyrazolopyridine core
(Table 6). Iodo diene 2v bearing a distal ester gave synthetically
useful yields and provided a handle for a variety of potential
functionalizations (entry 1). Simple alkyl-substituted vinyl ha-
lides (2x, 2y) constituted a limitation of the methodology affording
little or none of the desired products.20 However sp3 function-
ality could be introduced using cyclopropyl derivative 2w in a
good yield. We reason the viability of 2w was due to the high
s-character of the cyclopropane ring tuning the reactivity of the
double bond.
Reaction Scope: Pyridinium Ylide Derivatives. Having
demonstrated that a wide variety of alkenyl halides may be
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Table 5. Scope of (β)-Aryl Vinyl Halides
a 2.0 equiv of 1a and 1 equiv of the halide were used. b Yield of isolated product. c 4 equiv of 1a were used.
employed, we next considered substitution on the pyridinium
moiety (Table 7). We were pleased to note that a nitrile at the
4-position of the heterocyclic ring had little effect on the reaction
(entry 1). 3-Substituted pyridines bearing methyl and chloro
substituents reacted in good yields (entries 2 and 3). In both
cases, a slight preference was observed for reaction at the CÀH in
the less hindered 2-position. Both the isoquinolonium and
quinolonium ylides were viable partners (entries 4, 5), with the
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Table 6. Scope of Alternative Alkenyl Halides
Table 7. Scope of the Pyridinium in Coupling of Vinyl Halides
a 1.5 equiv 1a and 1 equiv of the halide were used. b Yield of isolated
product.
Scheme 4. Proposed Intermediate in the Synthesis of
2-Substituted Pyrazolopyridines
a Yield of isolated product.
(entry 1). When iodide 2a was submitted to the conditions in the
absence of silver benzoate, little of the iodide underwent
elimination to the alkyne (entry 2). Likewise, when 2a was mixed
with the silver salt in the absence of palladium, the major product
observed was indeed the recovered iodide (entry 3), indicating
that the silver benzoate alone is insufficient to promote
elimination. These results imply that the silver reagent is
effective in dehalogenating the palladated alkene following
oxidative addition by generating a highly reactive cationic
palladium species that readily undergoes β-hydride elimination
to form the alkyne (Scheme 5). Excess benzoate present in the
reaction medium could deprotonate the palladium hydride,
regenerating palladium(0) to resume the catalytic cycle.21 In
the absence of silver benzoate there is no driving force to coerce
the elimination, and presumably the oxidative addition is rever-
sible. Such a sequence would explain the decreased yields noted
with the Z-alkenyl iodide, as rapid syn β-hydride elimination is
latter giving the pyrazolopyridine derivative in excellent yield.
When the ylide derived from 6-methoxyquinoline was employed
the yield decreased to 69% (entry 6), suggesting a possible effect
of acidity at the 2-position of the ring in the transformation.
Finally, pyrazine ylide 1h furnished the desired 2-phenylpyrazo-
lopyrazine in 69% yield (entry 7).
Mechanistic Investigations and Catalytic Cycle. Intrigu-
ingly, as noted in Table 5, both E-, Z-(β)-arylvinyl iodide and
α-bromostyrene provided the same product, whereas the latter
substrate was expected to provide the 3-substituted pyrazolo[1,5-
a]pyridine (Scheme 4). We postulated that this could be the
result of elimination of HBr from the vinyl bromide to provide
phenylacetylene as a common reactive intermediate. To test this
hypothesis, we first examined whether β-styryl iodide could be
converted to phenyl acetylene under the reaction conditions in
the absence of the pyridinium ylide (Table 8). When submitted
to the full conditions, all of iodide 2a was converted to the alkyne
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Table 8. Studies into the Fate of the Alkenyl Iodide under the
Reaction Conditions
Scheme 7. Labeling Study in the Synthesis of 2-Substituted
Pyrazolopyridines from Vinyl Iodides and Phenylacetylene
entry
1
conditions
producta (%)
iodide 2a (1 equiv), PdBr2 (5 mol %), P(4-MeOPh)3
(15 mol %), AgOBz (4 equiv), 1,4-dioxane
(0.2 M), 125 °C, 16 h
B (>95)
Scheme 8. Directing Group Effect on the Synthesis of
Pyrazolopyridines
2
3
iodide 2a (1 equiv), PdBr2 (5 mol %), P(4-MeOPh)3
(15 mol %), 1,4-dioxane (0.2 M), 125 °C, 16 h
iodide 2a (1 equiv), AgOBz (4 equiv), dioxane
(0.2 M), 125 °C, 16 h
A (84)
A (73)
a Yields of isolated product.
Scheme 5. Proposed Pathway to the Formation of Alkynes
from Alkenyl Iodides
in the case of the alkenyl halides is the formation of the sp-
hybrized intermediate.
Scheme 6. Competition between 2p and Phenylacetylene
Next, a labeling study was undertaken to establish how the alkene
might couple to the pyridinium ylide. Both deuterated (E)-β-styryl
iodide and D-1-phenylacetylene were prepared and independently
employed as substrates under the optimal reaction conditions
(Scheme 7). No deuterium incorporation was observed in the final
product with either substrate. This suggested that the actual reactive
species involved in the CÀH insertion may be fully eliminated and
that the alkyne is deprotonated to form the silver acetylide.
We next considered the coupling/cyclization sequence. The
possibility of a formal [3 + 2] cyclization of the alkyne to the ylide
was rapidly ruled out. First, precedent with analogous N-amino-
pyridinium salts indicates that the product of such a process
would yield a 3-phenylpyrazolo[1,5-a]pyridine.5 To lend weight
toward this conclusion, the cyclization was attempted on the
2-vinylpyridinium ylide 3 accessed by our previously reported
copper-catalyzed direct alkenylation reaction (eq 2).14f Indeed,
when compound 3 was submitted to the complete reaction
conditions, the 2-phenylpyrazolopyridine was isolated in 56%
yield, suggesting that this could be a plausible intermediate, and
importantly that coupling prior to cyclization is feasible. How-
ever, the reduced yield and the observation of unreacted ylide in
the crude reaction mixture,22 in addition to the fact that no
alkenyl pyridine was ever observed during the reaction optimiza-
tion, is consistent with an alternative mechanistic pathway via the
alkyne. Interestingly, exclusion of either AgOBz or PdBr2 led to
no cyclization, implying that these reagents worked in concert to
not possible. In addition, vinyl iodides bearing alkyl groups were
nonoperative as the elimination to the alkyne was more difficult
for these substrates.
Second, phenylacetylene was submitted instead of iodide 2a
under the standard conditions, and 2-phenylpyrazolopyridine
was isolated in 56% yield (eq 1). The above results confirmed
that the alkyne could be generated in situ and provided very
strong evidence for the participation of an alkyne as a reaction
intermediate when using vinyl halides. Following this positive
result, a competition reaction was attempted between phenyl-
acetylene and high-yielding 4-fluoro-β-styryl bromide 2p
(Scheme 6). The reaction displayed 4:1 selectivity toward
the alkyne, suggesting that in the case of styryl halides, the
reaction proceeds quickly once the alkyne is formed. Indeed,
kinetic isotope effects of 1.7 and 1.5 were noted for 2a and
phenylacetylene, indicating that the CÀH bond breaking
event is not rate limiting and that the possible limiting step
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Scheme 9. Proposed Catalytic Cycle
Table 9. Scope of Alkyne Coupling Partners
effect the transformation from 3. Furthermore, the nature of the
ylide group had a significant effect on yield (Scheme 8). While
the benzoyl ylide 1a proved to be most reactive, increasing the
electron density of the ylide led to improved yields relative to when
electron poor groups are present (6 vs 7, and 8 vs 9). A reasonable
explanation is the improved Lewis basicity of the carbonyl group,
improving coordination to palladium and facilitating insertion of the
palladium in the α-position of the heterocycle.
a Yields of isolated product. b Yield based on recovered starting material.
inclusion of alkynes may both increase the breadth of potential
coupling partners and overcome some of the limitations of the
vinyl halides. A short optimization sequence (Table S1, Sup-
porting Information) improved the yield of the pyrazolopyr-
idine from 56% to 76% by the inclusion of an extra 1 equiv of
ylide and AgOBz. Here, the yield of pyrazolopyridine 4a using
phenylacetylene was comparable to that obtained with styryl iodide
2a (76% vs 78%), providing a complementary set of reaction
conditions. Most of the excess pyridinium ylide could be recovered
furnishing a yield of 95% based on recovered starting material
(Table 9, entry 1). It should also be noted that the reaction can be
performed under microwave irradiation whereby 2-phenylpyr-
azolopyridine was obtained in 62% isolated yield after 30 min
and 74% yield after 1 h at 125 °C. 1-Ethynylcyclohexene reacted
to give the desired pyrazolopyridine in 85% yield (entry 2). The
analogous 2-methyl-1-buten-3-yne only provided 29% of the
product (entry 3), though the low yield may be attributed to
the high volatility of the substrate. The use of alkynes permits
the introduction of various 2-alkyl substituents with a variety of
demands (entries 4À6). 3,3-Dimethyl-1-butyn, -1-octyne, and -
1-hexyne all reacted in moderate yield, demonstrating the
complimentarity of alkynes as substrates where alkyl substi-
tuted vinyl iodides were largely unreactive (Table 6). Methyl
10-undecynoate provided the product in 53% yield (entry 7),
and protected alcohol was also operative (entry 8). Internal
In our initial disclosure we proposed a catalytic cycle whereby
a palladium-catalyzed direct alkenylation occurred followed by a
silver-assisted cyclization.16 Following the studies described here
a revised cycle is proposed. First, PdBr2 undergoes a directed
insertion into the 2-position of the pyridinium ring (Scheme 9, A).
This may happen via σ-bond metathesis,17 generating HBr that
can be buffered by the excess benzoate. The palladated ylide then
may add across the silver acetylide giving the metallocycle B,
analogous to Fujiwara-type alkynylation reactions.23 The role of
the silver may be to activate the triple bond.24 It is possible that
vinyl iodides bearing alkyl groups were nonoperative as the
elimination to the alkyne is more difficult for these substrates.
When it was demonstrated that the uncyclized 2-vinyl ylide could
undergo the cyclization, similar Pd complexes had been reported,
as has Pd-catalyzed conjugate addition of amines.25 Reductive
elimination (C) then gives the cyclic intermediate that rear-
omatizes through the expulsion of the benzoyl moiety (D). This
may be assisted by the presence of Lewis acidic metal salts.
Protonolysis of the CÀAg bond at C3 upon workup or from
generated benzoic acids gives the observed product, explaining
the lack or deuterium incorporation in the labeling studies (E).
Reaction Scope: Alkynes. As a result of the mechanistic studies,
alkynes were identified as viable substrates for the reaction. We
next considered the scope of these substrates cognizant that the
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Table 10. Scope of the Pyridinium in the Synthesis of
2-Substituted Pyrazolopyridines from Alkynes
Table 11. Scope of 2,3-Disubstituted Pyrazolopyridines
a Yields of isolated product.
Scheme 10. Synthesis of 2-Phenyl-3-acetylpyrazolopyridine
Scheme 11. Proposed Reaction Pathway in the Synthesis of
2,3-Disubstituted Pyrazolopyridines
alkynes remained inoperative, adding weight to the proposed
requirement to form the silver acetylide.
The scope of the pyridinium ylide was investigated using
1-ethynylcyclohexene (Table 10). The isoquinolinium ylide
reacted well, affording the product in 71% yield (entry 1), and
the pyridazyl ylide 1h also displayed similar reactivity (entry 2).
As with the iodostyrene, substitution at the 3-position of
the ylide gave the product in 64% yield as an inseparable 3:1
mixture favoring the least hindered adduct (entry 3). The
2-alkenyl ylide reacted in only 21% (entry 3), though competi-
tion with the intramolecular cylization was noted.26
2-Picolonium Ylides. When the 2-picolonium ylide was applied
in the reaction the anticipated methylated pyrazolopyridine
was not observed. Instead the 2-phenyl, 3-acetyl pyrazolopyr-
idine was isolated in 29% yield (Scheme 10). The structure of
the product was confirmed through X-ray crystallography. The
palladium catalyst and silver benzoate were both needed to
effect the transformation, though 12 was still obtained without
employing styryl iodide 2a. Replacing AgOBz with AgOAc
improved reaction yields to 49% (Table 11, entry 1), presum-
ablydue to theimproved nucleophilicityofthe acetate. Converting
the benzoyl moiety to (3,5-trifluoromethyl)benzoyl or 4-meth-
oxybenzoyl afforded the corresponding products in 19% and
22% yield (entries 2 and 3). To date, all efforts to improve the
yields of these interesting 2,3-disubstituted products proved
unsuccessful. The reaction is believed to proceed as illu-
strated in Scheme 11. With the large excess of acetate relative
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to palladium, it is likely that the metal undergoes ligand
exchange to afford palladium acetate. The palladium(II)
species then undergoes addition to the benzylic position of
the picolonium ylide, presumably through an enamine intermedi-
ate due to the relative high acidity of the protons at that site,
analogously to our previous report. With no electrophile present,
and again due to the excess of acetate, reductive elimination occurs
to give the acetoxy intermediate A.27 An enamine intermediate
can then be regenerated an undergo silver-promoted cyclization/
condensation followed by rearomatization to give the observed
product 14.
phases were washed with 2.5 N NaOH. The organic phase was dried
over Na2SO4, filtered, and concentrated under reduced pressure to
afford the N-iminobenzoylpyridinium ylide.
N-Benzoyliminopyridinium Ylide (1a). The title compound was
prepared according to general procedure 1 using pyridine (1.24 mmol)
and benzoyl chloride. Compound 1a was isolated as a beige solid (236.0
mg, 96%). Characterization data was consistent with that reported in the
literature:15 mp 174 °C; 1H NMR (400 MHz, CDCl3) δ 8.81 (d, J = 5.9
Hz, 2H), 8.16 (d, J = 5.7 Hz, 2H), 7.87 (t, J = 7.6 Hz, 1H), 7.62 (t, J = 7.0
Hz, 2H), 7.48À7.37 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 170.8,
143.5, 137.4, 130.3, 128.1, 128.0, 126.1; IR (neat) 1548, 1465, 1332, 762,
710 cmÀ1; HRMS calcd for C12H10N2O [M]+ 198.0793, found
198.0798.
’ CONCLUSION
4-Cyano-N-benzoyliminopyridinium Ylide (1b). The title compound
was prepared according to general procedure 1 using 4-cyanopyridine
(1.24 mmol) and benzoyl chloride, but using a saturated aqueous
NaHCO3 solution instead of the aqueous NaOH solution. Compound
1b was obtained as a beige solid (116.7 mg, 42%). Characterization data
In summary, we have presented novel, facile methods for the
synthesis of 2-substituted pyrazolo[1,5-a]pyridines in two
steps from pyridine. Previous methods to prepare these
compounds either require multistep syntheses or require
substitution on the 3-position of the product that would
require further sequences for its removal. We solved these
problems by developing an efficient cascade direct elimina-
tion/functionalization/cyclization process. As the two steps
occur in tandem, the reaction is economical, and excess sub-
strates employed can be recovered and reused. The scope of
potential coupling partners tolerates a range of pyridinium
species in conjunction with complementary vinyl iodides,
bromides, and alkynes, which enable a wide range of groups
to be installed onto the heterocyclic core. The flexibility of the
reaction is likely due to the presence of a single reactive species,
allowing chemists a wide choice of possible reagents in the
preparation of these biologically relevant compounds.
1
was consistent with that reported in the literature:15 mp 184 °C; H
NMR (300 MHz, CDCl3) δ 9.34 (d, J = 6.4 Hz, 2H), 8.15 (d, J = 7.3 Hz,
2H), 7.79 (d, J = 6.1 Hz, 2H), 7.49À7.40 (m, 3H); 13C NMR (100 MHz,
CDCl3) δ 170.9, 142.4, 136.7, 131.3, 128.5 (2), 128.3, 117.2, 115.0; IR
(neat) 3097, 3048, 2237, 1587, 1557, 1543, 1436, 1319, 1291, 1164,
704 cmÀ1; LRMS (APCI, Pos) calcd for C13H9N3O [M + H]+ 224.1,
found 224.1.
3-Methyl-N-benzoyliminopyridinium Ylide (1c). The title com-
pound was prepared according to general procedure 1 using 3-picoline
(1.24 mmol) and benzoyl chloride. Compound 1c was obtained as a
white solid (258.9 mg, 99%). Characterization data was consistent with
1
that reported in the literature:15 mp 142 °C; H NMR (400 MHz,
CDCl3) δ 8.64 (s, 1H), 8.58 (d, J = 6.2 Hz,1H), 8.17À8.13 (m, 2H),
7.70 (d, J = 7.9 Hz, 1H), 7.54 (t, J = 6.5 Hz, 1H), 7.43À7.37 (m, 4H),
2.47 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 170.9, 143.5, 140.8, 138.0,
137.4, 137.2, 130.3, 128.1, 128.0, 125.6, 18.7; IR (neat) 3055, 1592,
1548, 1334, 705 cmÀ1. Anal. Calcd for C13H12N2O: C, 73.56; H, 5.70;
N, 13.20. Found: C, 73.49; H, 5.92; N, 13.02.
’ EXPERIMENTAL SECTION
General Considerations. All reactions were run under anaerobic
conditions (argon) with flame-dried glassware using standard techni-
ques for manipulating air-sensitive compounds. Anhydrous solvents
were obtained by filtration through drying columns or by distillation
over sodium and calcium hydride. Flash column chromatography was
performed using 230À400 mesh silica according to standard techniques.
Nuclear magnetic resonance spectra were recorded either on 300 or
400 MHzspectrometers. Chemicalshifts for1H NMR spectra are recorded
in ppm from tetramethylsilane with the solvent resonance as the internal
standard (chloroform, δ = 7.27 ppm). Data were reported as follows:
chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, m =
multiplet and br = broad), coupling constant in Hz and integration.
Chemical shifts for 13C NMR spectra were recorded in ppm from
tetramethylsilane using the central peak of deuterochloroform (77.36 ppm)
as the internal standard. High-resolution mass spectra were performed
by the Centre rꢀegional de spectroscopie de masse de l’Universitꢀe de
Montrꢀeal. Combustion analyses were performed by the Laboratoire
d’analyze ꢀelꢀementaire de l’Universitꢀe de Montrꢀeal. Reagents: commer-
cial reagents were used as supplied or purified by standard techniques
where necessary.
General Procedure 1: Synthesis of Pyridinium Ylides.
Pyridine derivative (1 equiv) and O-(2,4-dinitrophenyl)hydroxylamine
(1.2 equiv) were added to H2O/THF (1:1 mixture, 1.24 M). The
reaction flask was sealed with a septum, and the resulting suspension was
stirred at 40 °C for 16 h. During this period, the reaction mixture turned
dark red. The reaction was poured into aqueous NaOH (2.5 N, 6 Â vol)
at room temperature and stirred for 5 min, and then acyl/aryl chloride
(1.5 equiv) was added in one portion. After 5 h, the reaction was diluted
with H2O (5 Â vol) and extracted with CHCl3. The combined organic
3-Chloro-N-benzoyliminopyridinium Ylide (1d). The title com-
pound was prepared according to general procedure 1 using 3-chlor-
opyridine (1.24 mmol) and benzoyl chloride. Compound 1d was
obtained as a beige solid (271.6 mg, 94%). Characterization data was
consistent with that reported in the literature:15 mp 129 °C; 1H NMR
(400 MHz, CDCl3) δ 9.10 (s (br), 1H), 8.76 (d, J = 6.2 Hz, 1H), 8.13 (d,
J = 6.4 Hz, 2H), 7.79 (d, J = 8.2 Hz, 1H), 7.51 (t, J = 6.6 Hz, 1H),
7.49À7.35 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 170.6, 142.4,
141.0, 137.0, 136.3, 133.7, 130.5, 128.1, 128.0, 126.0; IR (neat) 3096,
1591, 1547, 1324, 711 cmÀ1; LRMS (APCI, Pos) calcd for C12H9ClN2O
[M + H]+ 233.0, found 233.0.
N-Benzoyliminoisoquinolinium Ylide (1e). The title compound was
prepared according to general procedure 1 using isoquinoline (1.24 mmol)
and benzoyl chloride, but adding benzoyl chloride first and letting it
react for 30 min before addition of the aqueous NaOH solution.
Compound 1e was obtained as a beige solid (290.2 mg, 93%). Charac-
terization data was consistent with that reported in the literature:15 mp
174 °C; 1H NMR (400 MHz, CDCl3) δ 9.89 (s, 1H), 8.43 (d, J = 6.9 Hz,
1H), 8.23À8.20 (m, 2H), 8.08 (t, J = 8.3 Hz, 1H), 7.98 (t, J = 6.6 Hz,
1H), 7.91 (t, J = 7.3 Hz, 1H), 7.83 (t, J = 7.6 Hz, 1H), 7.46À7.42
(m, 3H); 13C NMR (100 MHz, CDCl3) δ 171.0, 145.2, 137.6, 136.5,
134.1, 133.5, 130.3, 130.1, 128.5, 128.1, 128.0, 126.9, 124.1; IR (neat)
3053, 1590, 1546, 1336, 1298, 908, 707 cmÀ1; LRMS (APCI, Pos) calcd
for C16H13N2O [M + H]+ 249.1, found 249.1.
N-Benzoyliminoquinolinium Ylide (1f). The title compound was
prepared according to general procedure 1 using quinoline (1.24 mmol)
and benzoyl chloride, but adding BzCl first and letting it react for 30 min
before addition of the aqueous NaOH solution. Compound 1f was
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obtained as a beige solid (93%). Characterization data was consistent
with that reported in the literature:15 1H NMR (400 MHz, CDCl3)
δ 9.25 (d, J = 5.9 Hz, 1H), 8.85 (d, J = 8.9 Hz, 1H), 8.45 (d, J = 8.4 Hz,
1H), 8.35À8.30 (m, 2H), 8.05 (d, J = 8.2 Hz, 1H), 7.94 (t, J = 7.3 Hz,
1H), 7.81 (t, J = 7.4 Hz, 1H), 7.73 (dd, J = 8.3, 5.9 Hz, 1H), 7.50À7.47
(m, 3H); 13C NMR (100 MHz, CDCl3) δ 170.2, 145.5, 139.5, 138.3,
137.5, 133.2, 130.1, 129.9, 129.2, 128.5, 128.1, 127.9, 120.3, 120.1; IR
(neat) 3063, 1598, 1551, 1325, 1296, 714 cmÀ1; LRMS (APCI, Pos)
calcd for C16H13N2O [M + H]+ 249.1, found 249.1.
6-Methoxy-N-benzoyliminoquinolinium Ylide (1g). The title com-
pound was prepared according to general procedure 1 using 6-methox-
yquinoline (1.24 mmol) and benzoyl chloride, but adding BzCl first and
letting it react for 30 min before addition of the aqueous NaOH solution.
Compound 1g was obtained as a beige solid (96%). Characterization
data was consistent with that reported in the literature:15 mp 129 °C; 1H
NMR (400 MHz, CDCl3) δ 8.98 (dd, J = 5.9, 1.3 Hz, 1H), 8.66 (d, J =
9.6 Hz, 1H), 8.32À8.25 (m, 3H), 7.59 (dd, J = 8.4, 5.9 Hz, 1H),
7.51À7.44 (m, 4H), 7.20 (d, J = 2.7 Hz, 1H), 3.93 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 170.5, 157.4, 144.3, 137.3, 135.6, 130.9, 130.0, 129.5,
128.5, 127.8, 125.7, 123.1, 120.1, 119.9, 56.5; IR (neat) 3088, 1566,
1553, 1330, 915, 722 cmÀ1; LRMS (APCI, Pos) calcd for C17H15N2O2
[M + H]+ 279.31 m/z, observed 279.2 m/z.
N-Benzoyliminopyrazinium Ylide (1h). The title compound was
prepared according to general procedure 1 using pyrazine (1.24 mmol)
and benzoyl chloride. Compound 1h was obtained as a beige solid (46%).
Characterization data was consistent with that reported in the liter-
ature:15 mp 121 °C; 1H NMR (400 MHz, CDCl3) δ 9.30 (dd, J = 3.5, 1.4
Hz, 2H), 8.88 (dd, J = 3.5, 1.4 Hz, 2H), 8.19 (dd, J = 8.0, 1.3 Hz, 2H),
7.50À7.43 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 171.4, 148.6,
136.6, 133.3, 131.4, 128.5, 128.3; IR (neat) 3060, 1607, 1590, 1557,
1424, 1315, 1283, 1184, 709 cmÀ1; LRMS (APCI, Pos) calcd for
C11H10N3O [M + H]+ 200.1, found 200.1.
N-Trimethylacetyliminopyridinium Ylide (7). Pyridine (8.68 mmol)
and O-(2,4-dinitrophenyl)hydroxylamine (9.38 mmol) were mixed in
MeCN (15 mL). The reaction vessel was sealed, and the reaction was
stirred at 40 °C for 24 h. The reaction was concentrated, and the
resulting residue was triturated in three times with Et2O (100 mL). The
resulting solid was filtered and dried under vacuum to afford the N-
aminopyridinium salt (2.23 g, 98% yield). The salt (2.00 g, 15.0 mmol)
was dissolved in 10% aq NaOH (80 mL, 200.0 mmol) after which
pivaloyl chloride (9.3 mL, 75.0 mmol) was added dropwise over 45 min.
The solution was stirred for 20 h at room temperature, after which
saturated aq NaCl was added. Extraction with CH2Cl2 (5 Â 100 mL),
drying with Na2SO4, and removal of the solvent under reduced pressure
afforded 7 (2.67 g, 99% yield) as an off-white solid: mp 66 °C; 1H NMR
(300 MHz, CDCl3) δ 8.38 (d, J = 5.1 Hz, 2H), 7.70 (t, J = 7.8 Hz, 1H),
7.44 (t, J = 7.0 Hz, 2H), 1.10 (s, 9H); 13C NMR (75 MHz, CDCl3) δ
182.4, 143.4, 136.6, 125.6, 38.2, 28.2; IR (neat) 2955, 1556, 1392, 1213,
770, 680 cmÀ1; LRMS (APCI, pos) calcd for C10H15N2O [M + H]+
179.1, found 179.1.
N-(4-Trifluoromethylbenzoyl)iminopyridinium Ylide (8). The title
compound was prepared according to general procedure 1 using pyridine
(1.24 mmol) and 4-(trifluoromethyl)benzoyl chloride. Compound 8
was obtained as a yellow solid (267.3 mg, 81%): mp 165À170 °C: Rf =
0.63 (CH2Cl2/MeOH, 9/1); 1H NMR (300 MHz, CDCl3) δ 8.82À8.80
(m, 2H), 8.25 (d, J = 8.1 Hz, 2H), 7.97À7.91 (m, 1H), 7.68 (app dd, J =
14.3, 7.5 Hz, 4H); 13C NMR (100 MHz, CDCl3) δ 170.3, 144.1, 141.6,
138.1, 132.5 (q, J = 32.1 Hz), 129.2, 127.0, 125.6 (q, J = 3.7 Hz), 125.1
(q, J = 272.1 Hz); IR (neat) 3114, 3074, 1820, 1595, 1558, 1321,
1067 cmÀ1; HRMS calcd for C13H10F3N2O (M + H)+ 267.07397, found
267.07486.
N-(4-Methoxybenzoyl)iminopyridinium Ylide (9). The title com-
pound was prepared according to general procedure 1 using pyridine
(1.24 mmol) and 4-(methoxy)benzoyl chloride. Compound 9 was
obtained as a yellow oil (144.9 mg, 51%): Rf = 0.46 (CH2Cl2/MeOH,
9/1); 1H NMR (300 MHz, CDCl3) δ 8.72 (m, 2H), 8.09 (m, 2H), 7.82
(m, 1H), 7.57 (m, 2H), 6.89 (m, 2H), 3.80 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 163.7, 157.1, 147.0, 143.3, 136.7, 127.0, 123.6, 115.1,
4-Benzoyl-N-benzoyliminopyridinium Ylide (1i). The title compound
was prepared according to general procedure 1 using 4-benzoylpyridine
(1.24 mmol) and benzoyl chloride, but using a saturated aqueous
NaHCO3 solution instead of the aqueous NaOH solution. Compound
1i was obtained as a beige solid (0.282 mg, 75%). Characterization data
56.3; IR (neat) 3130, 3038, 2837, 1648, 1505, 1468, 1284, 1179 cmÀ1
;
HRMS calcd for C13H13N2O2 (M + H)+ 229.09267, found 229.09337.
2-Methyl-N-benzoyliminopyridinium Ylide (13a). The title com-
pound was prepared according to general procedure 1 using picoline
(1.24 mmol) and benzoyl chloride. Compound 13a was isolated as a
white solid (98% yield). Characterization data was consistent with that
reported in the literature:15 mp 111 °C; 1H NMR (400 MHz, CDCl3) δ
8.58 (d, J = 6.2 Hz, 1H), 8.19À8.15 (m, 2H), 7.80 (dt, J = 7.7, 1.3 Hz,
1H), 7.56 (d, J = 7.5 Hz, 1H), 7.41 (t, J = 7.5 Hz, 1H), 7.43À7.38 (m,
3H), 2.69 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 170.3, 154.3, 145.4,
137.8, 137.6, 130.5, 128.5, 128.4, 128.2, 128.1, 124.0, 19.9; IR (neat) 3054,
1593, 1553, 1491, 1330, 773, 707 cmÀ1. Anal. Calcd for C13H12N2O: C,
73.56; H, 5.70; N, 13.20. Found: C, 73.41; H, 6.09; N, 13.08.
1
was consistent with that reported in the literature:15 mp 179 °C; H
NMR (400 MHz, CDCl3) δ 9.13 (d, J = 7.1 Hz, 2H), 8.18 (dd, J = 7.6,
1.5 Hz, 2H), 7.92 (d, J = 7.1 Hz, 2H), 7.84À7.79 (m, 2H), 7.71 (t, J = 7.4
Hz, 1H), 7.57 (t, J = 7.8 Hz, 2H), 7.47À7.39 (m, 3H); 13C NMR (100
MHz, CDCl3) δ 191.8, 170.8, 142.9, 137.0, 135.2, 134.4, 132.9, 130.8,
130.2, 129.2, 128.3, 128.2, 126.0; IR (neat) 3106, 3080, 3049,1669,
1589, 1557, 1543, 1437, 1332, 1282, 1171, 713, 696 cmÀ1; LRMS
(APCI, Pos) calcd for C19H15N2O2 [M + H]+ 303.1, found 303.1.
N-Trifluoroacetyliminopyridinium Ylide (6). Pyridine (1.24 mmol)
and O-(2,4-dinitrophenyl) hydroxylamine (1.34 mmol) were mixed in
MeCN (1 mL). The reaction vessel was sealed, and the reaction was
stirred at 40 °C for 24 h. The reaction was concentrated, and the
resulting residue was triturated in three times with Et2O (10 mL). The
resulting solid was filtered and dried under vacuum to afford the N-
aminopyridinium salt (336 mg, 98% yield). The N-aminopyridinium
salt (0.812 mmol) was suspended in dichloromethane (5 mL). To this
was added K2CO3 (4.72 mmol) followed by trifluoroacetic anhydride
(0.974 mmol). The resulting mixture was stirred for 15 h at room
temperature, after which the solid was filtered. Concentration of the
2-Methyl-N-(3,5-trifluoromethylbenzoyl)iminopyridinium Ylide (13b).
The title compound was prepared according to general procedure 1
using picoline (1.24 mmol) and 3,5-(trifluoromethyl)benzoyl chloride
(1.84 mmol). Compound 13b was isolated as a white solid (77% yield):
1
Rf = 0.43 (CH2Cl2/MeOH, 95/5); mp 102À104 °C; H NMR (400
MHz, CDCl3) δ 8.67 (s, 2H), 8.62 (d, J = 6.3 Hz, 1H), 7.97À7.93
(m, 2H), 7.69À7.67 (m, 1H), 7.63À7.59 (m, 1H), 2.75 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 166.8, 153.7, 144.5, 139.6, 138.1, 131.0 (q,
J = 33 Hz), 128.3, 127.9, 123.8, 123.45 (q, J = 272.7 Hz), 123.4 (sept, J =
3.8 Hz), 19.3; IR (neat) 3100, 2928, 1630, 1593, 1282, 1113, 905, 736;
HRMS calcd for C15H11F6N2O (M + H)+ 349.07862, found 349.07701.
2-Methyl-N-(4-methoxybenzoyl)iminopyridinium Ylide (13c). The
title compound was prepared according to general procedure 1 using
picoline (1.24 mmol) and 4-methoxybenzoyl chloride. Compound 13c
was obtained as yellow oil (308.5 mg, 51%): Rf =0.43(CH2Cl2/MeOH, 9/1);
1
filtrate yielded 6 as a white solid (150 mg, 97% yield): mp 99 °C; H
NMR (300 MHz, CDCl3) δ 8.79 (d, J = 5.9 Hz, 2H), 8.10 (t, J = 7.7 Hz,
1H), 7.81 (t, J = 7.0 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 162.0 (q,
J = 34 Hz), 160.1, 142.5, 138.6, 126.3; 19F NMR (282 MHz, CDCl3)
δ À74.7; IR (neat) 3043, 1640, 1613, 1478, 1205, 1179, 1133,
771 cmÀ1; HRMS Calcd for C7H6F3N2O [M + H]+ 191.04267, found
191.05622.
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1H NMR (300 MHz, CDCl3) δ 8.63À8.61 (m, 1H), 8.16À8.12
(m, 2H), 7.86 (td, J = 7.8, 1.4 Hz, 1H), 7.61À7.59 (m, 1H),
7.55À7.50 (m, 1H), 6.95À6.92 (m, 2H), 3.86 (s, 3H), 2.72 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 170.5, 162. 1, 154.9, 146.0, 138.0, 130.4,
128.4, 124.4, 113.9, 56.3, 20.4; IR (neat) 3391, 3072, 2962, 1590, 1540,
1342, 1247, 1027 cmÀ1; HRMS calcd for C14H15N2O2 (M + H)+
243.11280, found 243.11377.
General Procedure 2: Synthesis of (E)-β-Aryl Vinyl Iodides
from Benzyl Bromides and CH2I2. Method A. A solution of CH2I2
(483 mL, 6.0 mmol) in THF (1.5 mL) was added dropwise to a solution
of NaHMDS (2.20 g, 12.0 mmol) in THF (8 mL) and ether (8 mL) at
À78 °C (dry ice/acetone bath) in the dark. After 20 min, a solution of
the benzyl bromide substrate (4.0 mmol) in THF (3 mL) was added
dropwise. The reaction mixture was stirred for 90 min and then removed
from the cold bath to warm to rt. After 30 min, DBU (0.597 mL, 4.0
mmol) was added dropwise and the solution stirred for 1 h before ether
(50 mL) was added. The mixture was filtered through a plug of Celite/
silica (approximately 3 cm Celite over 3 cm silica) and the solvent
removed under reduced pressure. The residue was purified by flash
chromatography to provide the pure vinyl iodide.
Method B. A solution of CH2I2 (644 mL, 8.0 mmol) in THF (1.9 mL)
was added dropwise to a solution of LiHMDS (1.34 g, 8.0 mmol) in
THF (8 mL) and ether (8 mL) at À78 °C (dry ice/acetone bath) in the
dark. After 20 min, a solution of the benzyl bromide substrate (4.0 mmol)
in THF (3 mL) was added dropwise. The reaction mixture was stirred
at À78 °C and allowed to warm to rt slowly over 16 h. After this time,
DBU (1.19 mL, 8.0 mmol) was added dropwise and the solution stirred
for 1 h before ether (50 mL) was added. The mixture was filtered
through a plug of Celite/silica (approximately 3 cm Celite over 3 cm
silica) and the solvent removed under reduced pressure. The residue was
purified by flash chromatography to provide the vinyl iodide. Where
necessary, residual CH2I2 following flash chromatography was removed
under high vacuum.
7.65 (s, 1H), 7.56 (d, J = 14.9 Hz, 1H), 7.46 (m, 3H), 6.94 (d, J = 14.9
Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 145.0, 135.0, 133.3, 133.1,
128.4, 128.2, 127.7, 126.6, 126.4, 126.2, 122.7, 77.0; IR (neat) 3049,
1599, 1585, 1507, 1433, 1293, 1216, 952, 765, 735 cmÀ1
.
(E)-1-(2-Iodovinyl)-2-methylbenzene (2h). Prepared according to
general procedure 2 (method A) starting from 2-methylbenzyl bromide
(740 mg, 4.0 mmol). Purification by flash chromatography (hexanes,
100%) afforded 2h as an off-white solid (879 mg, 90%, 99:1 E/Z).
Characterization data was consistent with that reported in the liter-
1
ature:18b Rf = 0.63 (hexanes, 100%); H NMR (300 MHz, CDCl3) δ
7.63 (d, J = 14.7 Hz, 1H), 7.32À7.11 (m, 4H), 6.68 (d, J = 14.7 Hz, 1H),
2.32 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 143.3, 136.9, 134.7, 130.3,
128.2, 126.2, 125.6, 77.7, 19.7; IR (neat) 3055, 3017, 2921, 1587, 1562,
1479, 1457, 1379, 1280, 1190, 947, 740 cmÀ1
.
(E)-1-(2-Iodovinyl)-4-methylbenzene (2i). Prepared according to
general procedure 2 (method A) starting from 4-methylbenzyl bromide
(740 mg, 4.0 mmol). Purification by flash chromatography (hexanes,
100%) afforded 2i as an off-white solid (906 mg, 93%, 99:1 E/). Character-
ization data was consistent with that reported in the literature:18b Rf =
0.54 (hexanes, 100%); 1H NMR (300 MHz, CDCl3) δ 7.40 (d, J = 14.9
Hz, 1H), 7.21À7.13 (m, 4H), 6.75 (d, J = 14.9 Hz, 1H), 2.35 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 144.7, 138.2, 134.9, 129.3, 125.8, 75.4,
21.3; IR (neat) 3053, 3029, 2915, 2859, 1608, 1591, 1561, 1509, 1379,
1280, 1189, 1172, 958, 765 cmÀ1
.
(E)-1-(2-Iodovinyl)-2-methoxybenzene (2k). Prepared according to
general procedure 2 (method B) starting from 2-methoxybenzyl bro-
mide (804 mg, 4.0 mmol). Purification by flash chromatography
(hexanes/Et2O, 95/5) afforded 2k as a yellow oil (784 mg, 75%, 98:2
E/). Characterization data was consistent with that reported in the
1
literature:14f Rf = 0.68 (Et2O/hexanes, 5/95); H NMR (400 MHz,
CDCl3) δ 7.70 (d, J = 14.9 Hz, 1H), 7.29 (t, J = 7.7 Hz, 2H), 6.97À6.88
(m, 3H), 3.88 (s, 3H).
(E)-1-(2-Iodovinyl)-3-methoxybenzene (2l). Prepared according to a
modification of general procedure 2 (method A) starting from 3-meth-
oxybenzyl bromide (834 mg, 4.1 mmol) and employing excess DBU
(900 μL, 6.0 mmol). Purification by flash chromatography (hexanes/
Et2O, 95/5) afforded 2l as a yellow oil (1.038 g, 95%, 99:1 E/Z).
Characterization data was consistent with that reported in the liter-
ature:18b Rf = 0.70 (hexanes/Et2O, 95/5); 1H NMR (400 MHz, CDCl3)
δ 7.43 (d, J = 14.9 Hz, 1H), 7.27 (t, J = 7.9 Hz, 1H), 6.93À6.85 (m, 4H),
3.84 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.6, 144.7, 138.8, 129.6,
118.5, 113.9, 111.2, 77.1, 55.2; IR (neat) 3057, 2999, 1596, 1572, 1490,
1428, 1313, 1284, 1261, 1152, 1048, 944, 757, 684 cmÀ1; HRMS calcd
for C9H9IO [M + H]+ 259.9693, found 259.9691.
(E)-(2-Iodovinyl)benzene (2a). Prepared according to general pro-
cedure 2 (method A) starting from benzyl bromide (684 mg, 4.0 mmol).
Purification by flash chromatography (hexanes, 100%) afforded 2a as a
yellow oil (849 mg, 92%, 98:2 E/Z). Characterization data was con-
sistent with that reported in the literature:18b Rf = 0.65 (hexanes, 100%);
1H NMR (300 MHz; CDCl3) δ 7.44 (d, J = 14.9 Hz, 1H), 7.38À7.27
(m, 5H), 6.84 (dd, J = 14.9, 1.8 Hz, 1H); 13C NMR (75 MHz; CDCl3) δ
145.0, 137.6, 128.7, 128.4, 126.0, 76.7; IR (neat) 3059, 3021, 1595, 1494,
1444, 1210, 1169, 1070, 945, 726, 688 cmÀ1
.
(Z)-1-Iodo-2-phenylethene (2b). Iodomethylenetriphenylphosphor-
ane (0.550 g, 1.0 mmol, 1.2 equiv) was added to a flame-dried flask with
stir bar. The flask was sealed with a septum, purged with argon, and
suspended in THF (2.3 mL). NaHMDS (1 mL of a 1 M solution) was
added slowly, and the resulting solution was cooled to À60 °C. HMPA
(0.3 mL) was added, and the solution was cooled further to À78 °C.
Benzaldehyde (0.082 mL, 0.8 mmol, 1 equiv) was added, and the mixture
was stirred at À78 °C for 1 min and then allowed to warm to rt over 35
min. Et2O (20 mL) was added, and the mixture was filtered over Celite.
Purification by chromatography yielded 2b as a yellow liquid (0.132 g,
72%). Characterization data was consistent with that reported in the
literature:18b Rf = 0.72 (hexanes, 100%); 1H NMR (300 MHz, CDCl3)
δ 7.68À7.60 (m, 2H), 7.39À7.34 (m, 3H), 7.30 (d, J = 8.5 Hz, 1H), 6.56
(d, J = 8.5 Hz, 1H).
(E)-1-(2-Iodovinyl)-4-benzyloxybenzene (2n). Prepared according to
a modification of general procedure 2 (method B) starting from
1-(benzyloxy)-4-(bromomethyl)benzene (1.11 g, 4.0 mmol) and em-
ploying excess DBU (1.8 mL, 12.0 mmol). Purification by flash chroma-
tography (hexanes/Et2O, 99/1) afforded 2n as an off-white solid (1.02 g,
76%, 99:1 E/Z). Characterization data was consistent with that reported
1
in the literature:18b Rf = 0.18 (hexanes/Et2O, 99/1); H NMR (300
MHz, CDCl3) δ 7.44À7.32 (m, 6H), 7.24À7.19 (m, 2H), 6.94À6.90
(m, 2H), 6.62 (d, J = 14.9 Hz, 1H), 5.05 (s, 2H); 13C NMR (75 MHz,
CDCl3) δ 158.9, 144.2, 136.6, 130.9, 128.6, 128.0, 127.44, 127.26, 115.0,
73.8, 70.0; IR (neat) 3054, 2932, 2868, 1600, 1508, 1454, 1377, 1281,
1181, 947, 836, 768, 747, 735 cmÀ1; HRMS calcd for C15H13IOAg [M +
Ag]+ 442.9057, found 442.9063.
(E)-4-(2-Iodovinyl)benzonitrile (2o). Prepared according to general
procedure 2 (method B) starting from 4-(bromomethyl)benzonitrile
756 mg, 4.0 mmol). Purification by flash chromatography (hexanes/
Et2O, 9/1) afforded 2o as a pale yellow solid (843 mg, 51%, 99:1 E/Z).
Characterization data was consistent with that reported in the liter-
ature:18b Rf = 0.34 (hexanes/Et2O 9/1); 1H NMR (300 MHz, CDCl3)
δ 7.59À7.56 (m, 2H), 7.40 (d, J = 15.0 Hz, 1H), 7.35À7.33 (m, 2H),
1,3-Bis-((E)-2-iodovinyl)benzene (2f). Prepared according to general
procedure 2, method A.
(E)-2-(2-Iodovinyl)naphthalene (2g). Prepared according to general
procedure 2 (method A) starting from 2-(bromomethyl)napthylene
(884 mg, 4.0 mmol). Purification by flash chromatography (hexanes, 100%)
afforded 2g as a yellow solid (782 mg, 70%, 98:2 E/Z). Characterization
data was consistent with that reported in the literature:18b Rf = 0.53
(hexanes, 100%); 1H NMR (300 MHz, CDCl3) δ 7.81À7.75 (m, 3H),
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ARTICLE
7.06 (d, J = 15.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 143.2, 141.4,
132.5, 126.3, 118.5, 111.5, 81.7; IR (neat) 3242, 3048, 2221, 1601, 1407,
1173, 937, 771 cmÀ1; HRMS calcd for C9H6INAg [M + Ag]+ 361.8590,
found 361.8596.
(petroleum ether/EtOAc, 95/5) to give 2v as a yellow liquid (9:1 E/Z).
Characterization data was consistent with that reported in the litera-
ture:14f Rf = 0.41 (petroleum ether/EtOAc, 9/1); 1H NMR (400 MHz,
CDCl3) δ 7.39 (ddd, J = 15.2, 10.3, 0.9 Hz, 1H), 6.90 (ddd, J = 11.2, 7.7,
0.8 Hz, 1H), 6.82 (ddd, J = 7.9, 0.8, 0.8 Hz, 1H), 6.10 (ddd, J = 15.2, 0.7,
0.7 Hz, 1H), 4.23 (q, J = 7.3 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H).
(E)-(2-(2-Iodovinyl)cyclopropyl)benzene (2w). A stirred solution of
DME (7.7 mL, 74.5 mmol, 2 equiv) in CH2Cl2 (170 mL) was cooled to
À15 °C. ZnEt2 (7.6 mL, 74.5 mmol, 2 equiv) was added dropwise while
the temperature of the solution was maintained below À14 °C. CH2I2
(12.0 mL, 149.0 mmol, 4 equiv) was added dropwise, maintaining the
reaction temperature below À6 °C. After the mixture was stirred for 10
min, a solution of cinnamyl alcohol (5.0 g, 37.3 mmol, 1 equiv) in
CH2Cl2 (30 mL) was added dropwise, keeping the reaction temperature
below À5 °C. The reaction was allowed to stir and warm to room
temperature over 16 h after which time saturated NH4Cl solution
(50 mL) was added followed by aqueous HCl (10%, 100 mL). The
mixture was diluted with Et2O (300 mL), and then the organic layer was
separated, washed with Na2SO3, NaHCO3, and saturated NaCl
solutions, dried over MgSO4, and concentrated. The crude cyclopro-
pane was purified with column chromatography (30% EtOAc/hexanes).
To remove residual unreacted cinnamyl alcohol following chromatog-
raphy, the product was dissolved in actone/water (1:1, 184 mL), and
then NMO (6.5 g, 55 mmol, 1.5 equiv) and OsO4 (0.061 M in t-BuOH,
15 mL, 2.5 mol %) were added. The reaction was stirred in the dark for
16 h and then diluted with Et2O and washed with Na2SO3 (100 mL).
The organic layer was removed, and the aqueous phase was extracted
with Et2O (3 Â 100 mL). The combined organic layers were washed
with NaHCO3 (100 mL) and brine, dried over MgSO4, and purified by
column chromatography (hexanes/EtOAc, 7/3) to give trans-2-phenyl-
cyclopropylmethanol (3.85 g, 26 mmol, 70%).
(E)-1-Fluoro-4-(2-iodovinyl)benzene (2p). Prepared according to
general procedure 2 (method A) starting from 4-fluorobenzyl bromide
(756 mg, 4.0 mmol). Purification by flash chromatography (hexanes,
100%) afforded 2p as a yellow solid (843 mg, 85%, 98:2 E/Z). Character-
ization data was consistent with that reported in the literature:18b Rf =
0.66 (hexanes, 100%); 1H NMR (300 MHz, CDCl3) δ 7.36 (d, J = 14.9
Hz, 1H), 7.27À7.22 (m, 2H), 7.02À6.95 (m, 2H), 6.73 (dd, J = 14.9, 0.6
Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 162.5 (d, J = 249 Hz), 143.7,
133.9 (d, J = 3 Hz), 127.6 (d, J = 8 Hz), 115.7 (d, J = 22 Hz), 76.1 (d, 2.5
Hz); IR (neat) 3056, 1598, 1578, 1505, 1230, 1172, 1157, 949, 837,
769 cmÀ1; HRMS calcd for C8H6FI [M]+ 247.9493, found 247.9493.
(E)-1-Chloro-2-(2-iodovinyl)benzene (2r). Prepared according to
general procedure 2 (method A) starting from 2-chlorobenzyl bromide
(823 mg, 4.0 mmol). Purificationbyflashchromatography(hexanes, 100%)
afforded 2r as a yellow oil (816 mg, 78%, 98:2 E/Z). Characterization data
was consistent with that reported in the literature:18b Rf = 0.75 (hexanes,
1
100%); H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 14.9 Hz, 1H),
7.42À7.33 (m, 2H), 7.26À7.21 (m, 2H), 6.90 (d, J = 14.9 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 141.2, 135.6, 132.0, 129.9, 129.2, 126.9,
126.7, 79.6; IR (neat) 3057, 1590, 1466, 1438, 1274, 1180, 1051, 946,
747 cmÀ1; HRMS calcd for C8H6ClI [M]+ 263.9197, found 263.9200.
(E)-1-Bromo-2-(2-iodovinyl)benzene (2s). Prepared according to
general procedure 2 (method B) starting from 2-bromobenzyl bromide
(1.0 g, 4.0 mmol). Purification by flash chromatography (hexanes,
100%) afforded 2s as a yellow oil (1.09 g, 87%, 98:2 E/Z). Characteriza-
tion data was consistent with that reported in the literature:18b Rf = 0.48
(hexanes, 100%); 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 14.8 Hz,
1H), 7.55 (dd, J = 7.9, 1.3 Hz, 1H), 7.40 (dd, J = 7.9, 1.7 Hz, 1H),
7.30À7.26 (m, 1H), 7.16 (td, J = 7.7, 1.7 Hz, 1H), 6.86 (d, J = 14.8 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ 143.7, 137.5, 132.9, 129.5, 127.6,
PCC (1.02 g, 4.8 mmol, 1.1 equiv) was added to a solution of trans-2-
phenylcyclopropylmethanol (0.630 g, 4.2 mmol, 1 equiv) in CH2Cl2
(25 mL). The solution was stirred for 14 h and filtered through silica and
Celite (hexanes/EtOAc, 7/3) to afford the cyclopropyl aldehyde (0.513 g,
3.6 mmol, 88%).
127.0, 122.3, 79.9; IR (neat) 3056, 1587, 1461, 1027, 945, 743 cmÀ1
.
(E)-1-Bromo-3-(2-iodovinyl)benzene (2u). Prepared according to
general procedure 2 (method B) starting from 3-bromobenzyl bromide
(1.0 g, 4.0 mmol). Purification by flash chromatography (hexanes,
100%) afforded 2u as a yellow oil (1.08 g, 87%, 98:2 E/Z). Character-
ization data was consistent with that reported in the literature:18b Rf =
0.56 (hexanes, 100%); 1H NMR (300 MHz, CDCl3) δ 7.42À7.37 (m,
2H), 7.33 (d, J = 14.9 Hz, 1H), 7.20À7.14 (m, 2H), 6.87 (d, J = 14.9 Hz,
1H); 13CNMR (75 MHz, CDCl3) δ143.3, 139.4, 131.1, 130.1, 128.8, 124.5,
CrCl2 (3.10 g, 25.2 mmol, 7 equiv) was dissolved in THF (20 mL)
and the mixture cooled to 0 °C. The previously prepared cyclopropyl
aldehyde (0.513 g, 3.6 mmol, 1 equiv) and iodoform (2.83 g, 7.2 mmol,
2 equiv) were dissolved in THF (15 mL). The aldehyde/iodoform
solution was added to the CrCl2 solution at 0 °C via syringe, and the
mixture was allowed to stir for 3 h. Water (100 mL) was added, and the
organic layer was separated. The aqueous phase was extracted with Et2O
(3 Â 100 mL), and the combined organic layers were dried with
Na2SO4, concentrated, and purified by column chromatography (hexanes,
100%) to afford the title compound 2w as a colorless oil (0.608 g, 61%,
7.5:1 E/Z). Characterization data was consistent with that reported in
the literature:14f Rf = 0.55 (hexanes, 100%); 1H NMR (300 MHz,
CDCl3) δ 7.29 (t, J = 7.3 Hz, 2H), 7.20 (d, J = 7.3 Hz, 1H), 7.09 (d, J =
7.3 Hz, 2H), 6.20 (dd, J = 14.4, 8.8 Hz, 1H), 6.04 (d, J = 14.4 Hz, 1H),
2.03 (m, 1H), 1.74 (m, 1H), 1.29 (m, 1H), 1.18 (m, 1H); 13C NMR (75
MHz, CDCl3) δ 147.9, 141.3, 128.4, 125.9, 125.7, 71.8, 29.5, 24.7, 16.1;
IR (neat) 3025, 1604, 1495, 1458, 1277, 1199, 1180, 1127, 1073,
942 cmÀ1; GCMS calcd for C11H11I 269.99, found 270.01.
1-Iodocyclohexene (2x). Cyclohexanone (5.2 mL, 50 mmol, 1 equiv)
was added dropwise over 5À10 min to hydrazine monohydrate (15 mL,
310 mmol, 6 equiv) with vigorous stirring. A white precipitate formed,
and the reaction mixture was refluxed at 150 °C for 2 h. The mixture was
cooled to room temperature, and then water (100 mL) was added. The
organic layer was separated, and the aqueous phase was extracted with
CH2Cl2 (100 mL). The combined organic layers were washed with
saturated NaCl solution (50 mL), dried with Na2SO4, and concentrated
to give the crude hydrazone. Tetramethylguanidine (37 mL, 300 mmol,
6 equiv) in THF (55 mL) was added to iodine (14 g, 300 mmol, 6 equiv)
122.8, 78.7; IR (neat) 3056, 1590, 1557, 1474, 1209, 1071, 942, 755 cmÀ1
.
Ethyl (2E,4Z)-5-Iodopenta-2,4-dienoate (2v). To a solution of ethyl
(Z)-β-iodoacrylate (5.0 mL, 39 mmol, 1 equiv) in CH2Cl2 (90 mL) at
À78 °C was added DIBAL (43 mmol, 1.1 equiv) over 10 min. After
being stirred for 5 min, the reaction was quenched with MeOH
(7.0 mL), followed by aqueous sodium potassium tartrate (200 mL).
Following warming to room temperature, Et2O (100 mL) was added,
and the mixture was stirred for 1 h and then further diluted with Et2O
and water (50 mL). The organic layer was separated, and the aqueous
phase was extracted with Et2O (4 Â 80 mL). The combined organic
extracts were washed with brine, dried with K2CO3, and concentrated to
give the crude aldehyde. Separately, trimethyl phosphonoacetate
(8.20 mL, 41 mmol, 1.1 equiv) in THF (80 mL) was cooled to
À78 °C. To this solution was added n-BuLi (1.7 M in hexanes, 41
mmol, 1.1 equiv), and the solution was stirred for 30 min. The previously
prepared aldehyde in THF (40 mL) was then added via cannula. The
reaction mixture was allowed to warm to rt over 2 h and then stirred at rt
for 1 h after which Et2O/water (50/50, 100 mL) was added. The organic
layer was separated, and the aqueous phase was extracted 4Â with Et2O.
The combined organic extracts were washed with brine, dried with
Mg2SO4, concentrated, and purified via column chromatography
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The Journal of Organic Chemistry
ARTICLE
in THF (80 mL). The resulting solution was added via cannula to the
crude hydrazone (2.8 g) in THF (25 mL) at 0 °C. The reaction mixture
was allowed to warm to room temperature overnight, refluxed for 2 h at
85 °C, and then cooled to room temperature. The organic layer was
washed with aqueous HCl (1 M, 100 mL) and saturated NaCl solution.
The aqueous layer was extracted with Et2O (2 Â 100 mL), dried with
MgSO4, concentrated, and purified via column chromatography
(hexanes, 100%) to give 2x as a colorless oil (0.970 g, 20% over two
steps). Characterization data was consistent with that reported in the
(hexanes/Et2O, 95/5) afforded 2m as a white solid (153 mg, 72%, >99:1
E:Z). Characterization data was consistent with that reported in the
1
literature:18b Rf = 0.46 (hexanes/Et2O, 95/5); H NMR (300 MHz,
CDCl3) δ 7.24À7.20 (m, 2H), 7.02 (d, J = 13.9 Hz, 1H), 6.85À6.82
(m, 2H), 6.59 (d, J = 13.9 Hz, 1H), 3.79 (s, 3H). 13C NMR (75 MHz,
CDCl3) δ 159.5, 136.4, 128.6, 127.2, 114.1, 103.9, 55.2; IR (neat) 3067,
2932, 2837, 1605, 1510, 1460, 1254, 1177, 1028, 776 cmÀ1
.
(E)-1-Fluoro-4-(2-bromovinyl)benzene (2q). Prepared according to
the general procedure for vinyl bromides starting from 4-fluorobenzyl
bromide (189 mg, 1.0 mmol). Purification by flash chromatography
(hexanes, 100%) afforded 2q as a colorless oil (159 mg, 79%, >99:1 E/Z).
Characterization data was consistent with that reported in the litera-
ture:18b Rf = 0.53 (hexanes, 100%); 1H NMR (300 MHz, CDCl3)
δ 7.27À7.22 (m, 2H), 7.07À6.97 (m, 3H), 6.67 (dd, J = 14.0, 0.4 Hz,
1H); 13C NMR (75 MHz; CDCl3) δ 162.6 (d, J = 248 Hz), 136.0, 132.1
(d, J = 3 Hz), 127.7 (d, J = 8 Hz), 115.8 (d, J = 22 Hz), 106.9 (d, 2.5 Hz);
1
literature:28 Rf = 0.8 (hexanes, 100%); H NMR (400 MHz, CDCl3)
δ 6.32 (m, 1H), 2.51 (m, 2H), 2.10 (m, 2H), 1.60À1.70 (m, 4H).
1-Iodopentene (2y). To a flame-dried round-bottomed flask were
added pentyne (4.2 mL, 42.6 mmol, 1.0 equiv) and hexanes (50 mL).
The solution was cooled to À78 °C after which DIBAL (9.5 mL, 53.3
mmol, 1.3 equiv) was added over 30 min. The reaction temperature was
warmed to rt overnight and then cooled to À78 °C. Iodine (13.8 g, 54.3
mmol, 1.3 equiv) was dissolved in THF (50 mL) and added via syringe.
The solution was allowed to stir at À78 °C for 30 min and allowed to stir
at rt for 1 h. The solution was poured onto 100 mL of iced 1 M HCl, and
an additional 100 mL 1 M HCl was added. The organic layer was
separated, and the aqueous phase was extracted with 3 Â 100 mL of
pentane. The organic layers were combined, washed with satd NaHCO3
solution (2 Â 100 mL), satd Na2S2O3 solution (2 Â 100 mL), and satd
NaCl solution (2 Â 100 mL), and then dried with MgSO4. Filtration
through a pad of silca and concentration afforded 2y as a clear liquid
(1.92 g, 9:1 E/Z, 25%). Characterization data was consistent with that
IR (neat) 3056, 1590, 1557, 1474, 1421, 1209, 1071, 942, 755 cmÀ1
.
(E)-1-Bromo-2-(2-bromovinyl)benzene (2t). Prepared according to
the general procedure for vinyl bromides starting from 2-bromobenzyl
bromide (250 mg, 1.0 mmol). Purification by flash chromatography
(hexanes, 100%) afforded 2t as a colorless oil (175 mg, 67%, >99:1 E/Z).
Characterization data was consistent with that reported in the
literature:18b Rf = 0.56 (hexanes, 100%); 1H NMR (300 MHz, CDCl3)
δ 7.55À7.52 (m, 1H), 7.42 (d, J = 13.9 Hz, 1H), 7.38À7.35 (m, 1H),
7.28À7.23 (m, 1H), 7.16À7.11 (m, 1H), 6.74 (d, J = 13.9 Hz, 1H); 13C
NMR (75 MHz, CDCl3) δ 136.2, 135.9, 133.1, 129.6, 127.6, 127.1, 122.7,
109.2; IR (neat) 3069, 1603, 1463, 1435, 1219, 1020, 931, 740 cmÀ1
(E)-(2-Chlorovinyl)benzene (2e). Chloroiodomethane (109 μL, 1.5
mmol) was added dropwise to a solution of NaHMDS (550 mg, 3.0
mmol) in THF (2 mL) and ether (2 mL) at À78 °C (dry ice/acetone
bath) in the dark. After 20 min, a solution of the benzyl bromide (171 mg,
1.0 mmol) in THF (1 mL) was added dropwise. The reaction mixture
was stirred at À78 °C, and then the mixture was allowed to warm to rt
slowly over 16 h. Ether (50 mL) was added, the mixture was filtered
through a plug of Celite/silica (approximately 3 cm Celite over 3 cm
silica), and the solvent was removed under reduced pressure. The
residue was purified by flash chromatography (hexanes, 100%) to
provide 2e as a colorless oil (123 mg, 89%, 97:3 E/Z. Characterization
data was consistent with that reported in the literature:18b Rf = 0.60
(hexanes, 100%); 1H NMR (300 MHz, CDCl3) δ 7.38À7.26 (m, 5H),
6.86 (d, J = 13.7 Hz, 1H), 6.66 (dd, J = 13.7, 0.5 Hz, 1H); 13C NMR (75
MHz, CDCl3) δ 134.8, 133.2, 128.7, 128.1, 126.1, 118.7; IR (neat) 3076,
1
previously reported in the literature:29 Rf = 0.81 (hexanes, 100%); H
NMR (400 MHz, CDCl3) δ 6.51 (dt, J = 14.5, 1.5 Hz, 1H), 5.96 (dt, J =
14.5, 1.5 Hz, 1H), 2.03 (m, 2H), 1.43 (s, J = 7.5 Hz, 2H), 0.91 (t, J = 7.5
Hz, 3H).
General Procedure 3: Synthesis of (E)-β-Aryl Vinyl Bro-
mides from Benzyl Bromides and CH2Br2. Dibromomethane
(281 μL, 4 mmol) was added dropwise to a solution of NaHMDS
(550 mg, 3.0 mmol) in THF (2 mL) and ether (2 mL) at À78 °C (dry
ice/acetone bath) in the dark. After 20 min, a solution of the benzyl
bromide substrate (1.0 mmol) in THF (1 mL) was added dropwise. The
reaction mixture was maintained at À78 °C for at least 3 h, stirring was
continued at À78 °C, and then the mixture was allowed to warm to rt
slowly over 16 h. Ether (50 mL) was added, and then the mixture was
filtered through a plug of Celite/silica (approximately 3 cm Celite over
3 cm silica) and the solvent removed under reduced pressure. The residue
was purified by flash chromatography to provide the vinyl bromide.
(E)-(2-Bromovinyl)benzene (2c). Prepared according to general
procedure 3 starting from benzyl bromide (171 mg, 1.0 mmol). Puri-
fication by flash chromatography (hexanes, 100%) afforded 2c as a
colorless oil (127 mg, 69%, 99:1 E/). Characterization data was con-
sistent with that reported in the literature:18b Rf = 0.60 (hexanes, 100%);
1H NMR (300 MHz; CDCl3) δ 7.37À7.29 (m, 5H), 7.12 (d, J = 14.0 Hz,
1H), 6.78 (d, J = 14.0 Hz, 1H); 13C NMR (75 MHz; CDCl3) δ 137.1,
135.9, 128.8, 128.2, 126.1, 106.5; IR (neat) 3074, 3024, 1607, 1445,
3025, 1607, 1573, 1497, 1446, 1245, 1073, 936, 737, 691 cmÀ1
.
General Procedure 4: Synthesis of 2-Substituted Pyrazolo-
[1,5-a]pyridines from Vinyl Halides. To a 3 mL conical microwave
vial equipped with a spin vane was added pyridinium ylide (1.0 mmol, 2
equiv). In a glovebox were added p-tris(methoxyphenyl)phosphine
(0.15 equiv), palladium bromide (0.05 equiv), and silver benzoate
(1.5 mmol, 3 equiv), and the microwave vial was crimped shut. The
alkenyl iodide derivative (0.5 mmol, 1 equiv) was dissolved in 1,4-dioxane
(0.5 mL) and added via syringe. The syringe was rinsed three times with
0.5 mL of dioxane to reach a final volume of 2 mL. The solution was
heated to 125 °C with fast stirring. Within 5 min, a color change was
observed. The mixture was stirred for 16 h and then cooled to room
temperature. Dichloromethane was added, and the precipitate was
filtered through a cotton plug and washed with dichloromethane.
Saturated sodium bicarbonate was added, and the organic phase was
extracted with dichloromethane (3 Â 50 mL). The solution was dried
with Na2SO4, concentrated under reduced pressure, and purified via
column chromatography to afford the title compounds.
730 cmÀ1
.
(E)-1-(2-Bromovinyl)-4-methylbenzene (2j). Prepared according to
general procedure 3 for vinyl bromides starting from 4-methylbenzyl
bromide (186 mg, 1.0 mmol). Purification by flash chromatography
(hexanes, 100%) afforded 2j as a white solid (179 mg, 91%, >99:1 E/Z).
Characterization data was consistent with that previously reported in the
literature:18b Rf = 0.59 (hexanes, 100%); 1H NMR (300 MHz; CDCl3) δ
7.24À7.12 (m, 4H), 7.08 (d, J = 14.0 Hz, 1H), 6.71 (d, J = 14.0 Hz, 1H),
2.34 (s, 3H); 13C NMR (75 MHz; CDCl3) δ 138.1, 136.9, 133.1, 129.4,
125.9, 105.4, 21.2; IR (neat) 3070, 2914, 1602, 1509, 1226, 1194, 949,
907, 825, 769, 725 cmÀ1
.
2-Phenylpyrazolo[1,5-a]pyridine (4a). The title compound was
prepared according to general procedure 4 using 0.5 mmol of (E)-(2-
iodovinyl)benzene. Purification by column chromatography (CH2Cl2/
hexanes, 95/5) afforded 4a as a light yellow powder (75.3 mg, 78%).
(E)-1-(2-Bromovinyl)-4-methoxybenzene (2m). Prepared according
to the general procedure for vinyl bromides starting from 4-methoxy-
benzyl bromide (201 mg, 1.0 mmol). Purification by flash chromatography
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ARTICLE
Characterization data was consistent with that reported in the liter-
753 cmÀ1; HRMS calcd for C14H13N2O [M + H]+ 225.1022, found
225.1015.
1
ature:16 Rf = 0.79 (CH2Cl2, 100%); mp 110À113 °C; H NMR (300
2-(3-Methoxyphenyl)pyrazolo[1,5-a]pyridine (4g). The title com-
pound was prepared according to general procedure 4 using 0.5 mmol of
2l. Purification by column chromatography (CH2Cl2, 100%) afforded
4g as a yellow powder (73.4 mg, 65%). Characterization data was con-
sistent with that reported in the literature:16 Rf = 0.23 (CH2Cl2, 100%);
mp 43À45 °C; 1H NMR (300 MHz, CDCl3) δ 8.48 (d, J = 6.9 Hz, 1H),
7.58À7.52 (m, 2H), 7.49 (d, J = 9.0 Hz, 1H), 7.36 (t, J = 8.3 Hz, 1H),
7.06 (t, J = 6.9 Hz, 1H), 6.93 (d, J = 8.1 Hz, 1H); 6.79 (s, 1H), 6.71 (t, J =
6.9 Hz, 1H), 3.36 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 160.8, 154.2,
142.3, 135.6, 130.6, 129.4, 123.7, 119.9, 118.7, 115.1, 112.6, 112.4, 94.8,
56.0; IR (neat) 2833, 1603, 1583, 1520, 1470, 1245, 1158, 1041, 768,
737 cmÀ1; HRMS calcd for C14H13N2O [M + H]+ 225.10224, found
225.10151.
2-(4-Methoxyphenyl)pyrazolo[1,5-a]pyridine (4h). The title com-
pound was prepared according to General Procedure 4 using 0.5 mmol
of 2m. Purification by column chromatography (CH2Cl2, 100%) afforded
4h as a yellow powder (72.4 mg, 63%): Rf = 0.23 (CH2Cl2, 100%); mp
100À101 °C; 1H NMR (300 MHz, CDCl3) δ 8.45 (d, J = 6.9 Hz, 1H),
7.93À7.88 (m, 2H), 7.47 (d, J = 8.9 Hz, 1H), 7.09À6.97 (m, 3H),
6.72À6.67 (m, 2H), 3.86 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 160.7,
154.3, 142.5, 129.3, 128.6, 126.8, 124.2, 118.5, 115.0, 112.2, 93.9, 56.2;
IR (neat) 3076, 2954, 1631, 1514, 1243, 1178, 842, 771 cmÀ1; HRMS
calcd for C14H13N2O [M + H]+ 225.10224, found 225.10223.
2-[4-(Benzyloxy)phenyl]pyrazolo[1,5-a]pyridine (4i). The title com-
pound was prepared according to General Procedure 4 using 0.5 mmol
of 2n. Purification by column chromatography (CH2Cl2, 100%)
afforded 4i as a light yellow powder (131 mg, 87%). Characterization
data was consistent with that reported in the literature:16 Rf = 0.24
(CH2Cl2, 100%); mp 164 °C; 1H NMR (300 MHz, CDCl3) δ 8.47 (d,
J = 6.9 Hz, 1H), 7.92 (d, J = 9.0 Hz, 2H), 7.50À7.31 (m, 6H), 7.10À7.04
(m, 3H), 6.73À6.67 (m, 2H), 5.13 (s, 2H); 13C NMR (75 MHz, CDCl3)
δ 160.1, 154.4, 142.5, 137.9, 129.5, 129.3, 128.8, 128.6, 128.4, 127.1,
124.3, 118.6, 115.9, 112.2, 93.9, 71.0; IR (neat) 3031, 1612, 1451, 1250,
836, 725 cmÀ1; HRMS calcd for C20H17N2O [M + H]+ 301.13354,
found 301.13310.
4-Pyrazolo[1,5-a]pyridin-2-ylbenzonitrile (4j). The title compound
was prepared according to general procedure 4 using 0.5 mmol of 2o.
Purification by column chromatography (CH2Cl2/hexanes, 9/1) af-
forded 4j as a yellow powder (67 mg, 61%). Characterization data was
consistent with that reported in the literature:16 Rf = 0.63 (CH2Cl2,
100%); 1H NMR (300 MHz, CDCl3) δ 8.46 (d, J = 6.9 Hz, 1H), 8.05 (d,
J = 8.4 Hz, 2H), 7.72 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 9.3 Hz, 1H), 7.13 (t,
J = 7.9 Hz, 1H), 6.84 (s, 1H), 6.80 (t, J = 6.6 Hz, 1H); 13C NMR (75
MHz, CDCl3) δ 152.3, 142.7, 138.7, 133.2, 129.6, 127.7, 124.6, 119.9,
119.1, 113.4, 112.5, 95.3; IR (neat) 3032, 2223, 1632, 1505, 1427, 842,
753 cmÀ1; HRMS calcd for C14H10N3 [M + H]+ 220.08692, found
220.08626.
2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridine (4k). The title com-
pound was prepared according to general procedure 4 using 0.5 mmol
of 2p. Purification by column chromatography (CH2Cl2/hexanes, 95/5)
afforded 4k as a beige powder (96.4 mg, 86%). Characterization data was
consistent with that reported in the literature:16 Rf = 0.79 (CH2Cl2,
100%); mp 145À147 °C; 1H NMR (300 MHz, CDCl3) δ 8.48 (d, J = 6.3
Hz, 1H), 7.95À7.90 (m, 2H), 7.48 (d, J = 8.4 Hz, 1H), 7.18À7.02 (m,
3H), 6.75À6.69 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 163.3 (d, J =
247.2 Hz), 153.5, 142.5, 130.3 (d, J = 3.3 Hz), 129.3, 129.0 (d, J = 9.1
Hz), 124.4, 118.7, 116.5 (d, J = 21.7 Hz), 112.6, 94.3; IR (neat) 1630,
1599, 1512, 1473, 1429, 1213, 772, 745 cmÀ1; HRMS calcd for
C13H10FN2 [M + H]+ 213.08225, found 213.08138.
MHz, CDCl3) δ 8.47 (d, J = 6.9 Hz, 1H), 7.97 (d, J = 7.5 Hz, 2H),
7.54À7.34 (m, 3H), 7.08 (t, J = 7.8 Hz, 1H), 6.80 (s, 1H), 6.73 (t, J = 6.8
Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 154.2, 142.5, 134.2, 129.4,
129.3, 129.2, 124.2, 122.3, 118.7, 112.7, 94.4; IR (neat) 3086, 1630,
1508, 1467, 1327, 763, 688 cmÀ1; HRMS calcd for C13H11N2 [M + H]+
195.09167, found 195.09088.
1,3-Di(pyrazolo[1,5-a]pyridin-2-yl)benzene (4b). The title compound
was prepared according to General Procedure 4 using 0.244 mmol of 2f.
Purification by column chromatography (toluene/EtOAc, 6/4) afforded
4b as a light yellow oil in (75.3 mg, 40%): Rf = 0.80 (toluene/EtOAc, 6/
4); 1H NMR (400 MHz, CDCl3) δ 8.58À8.57 (m, 1H), 8.54 (dd, J = 7.0,
1.0 Hz 2H), 8.00 (dd, J = 7.7, 1.7 Hz 2H), 7.59À7.54 (m, 3H),
7.15À7.11 (m, 2H), 6.93À6.92 (s, 2H), 6.79À6.75 (dt, J = 6.9, 1.4
Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 153.1, 141.2, 133.4, 128.9,
128.2, 126.1, 124.3, 123.0, 117.6, 111.4, 93.6; IR (neat) 3077, 2975,
1634, 1256, 770 cmÀ1; HRMS calcd for C20H15N4 [M + H]+ 311.12912,
found 311.12912.
2-(Naphthalen-2-yl)pyrazolo[1,5-a]pyridine (4c). The title com-
pound was prepared according to general procedure 4 using 0.5 mmol
of 2g. Purification by column chromatography (hexanes/CH2Cl2, 1:1)
afforded 4c as a light yellow/orange powder (75.6 mg, 61%): Rf = 0.79
(CH2Cl2, 100%); mp 61 °C; 1H NMR (300 MHz, CDCl3) δ 8.53 (d, J =
7.0 Hz, 1H), 8.49 (s, 1H), 8.13 (dd, J = 8.5, 1.4 Hz, 1H), 7.95 (dd, J = 8.8,
3.6 Hz, 2H), 7.90À7.87 (m, 1H), 7.55À7.48 (m, 3H), 7.09 (m, 1H),
6.93 (s, 1H), 6.75 (t, J = 6.9 Hz, 1H); 13C NMR (75 MHz, CDCl3)
δ 154.2, 142.5, 134.2, 129.4, 129.2, 124.2, 118.7, 112.7, 94.4; IR (neat)
3104, 3051, 2918, 1632, 1506, 1497, 1327, 1254, 1141, 827, 777 cmÀ1
;
HRMS calcd for C17H13N2 [M + H]+ 245.10732, found 245.10732.
2-(2-Methylphenyl)pyrazolo[1,5-a]pyridine (4d). The titlecompound
was prepared according to general procedure 4 using 0.5 mmol of 2h.
Purification by column chromatography (CH2Cl2, 100%) afforded 4d as
a light beige powder (73.3 mg, 70%). Characterization data was con-
sistent with that reported in the literature:16 Rf = 0.27 (CH2Cl2, 100%);
mp 59À63 °C; 1H NMR (300 MHz, CDCl3) δ = 8.52 (d, J = 6.9 Hz,
1H), 7.75À7.67 (m, 1H), 7.55 (d, J = 9.6 Hz, 1H), 7.30 (s, 3H), 7.12 (t,
J = 6.8 Hz 1H), 6. 75 (m, 1H), 6.65 (s, 1H); 2.56 (s, 3H); 13C NMR (75
MHz, CDCl3) δ = 154.9, 141.8, 137.4, 134.0, 131.8, 130.8, 129.3, 129.2,
126.8, 124.3, 118.7, 112.4, 97.8, 22.2; IR (neat) 1720, 1631, 1507, 1459,
1328, 759, 724 cmÀ1; HRMS calcd for C14H13N2 [M + H]+ 209.10732,
found 209.10685.
2-(4-Methylphenyl)pyrazolo[1,5-a]pyridine (4e). The title compound
was prepared according to general procedure 4 using 0.5 mmol of 2i.
Purification by column chromatography (CH2Cl2, 100%) afforded 4e as
a light beige powder in (82.5 mg, 79%). Characterization data was
consistent with that reported in the literature:16 Rf = 0.23 (CH2Cl2/
hexanes, 9/1); mp 117À118 °C; 1H NMR (300 MHz, CDCl3) δ = 8.49
(d J = 6.9 Hz, 1H), 7.90 (d, J = 8.1 Hz, 2H), 7.50 (d, J = 9.3 Hz, 1H), 7.30
(d, J = 8.1 Hz, 2H), 7.08 (t, J = 8.0 Hz 1H), 6.77 (s, 1H), 6.72 (t, J = 6.9
Hz, 1H), 2.41 (s, 3H); 13C NMR (75 MHz, CDCl3) δ = 154.5, 142.6,
139.4, 131.4, 130.3, 129.2, 127.8, 124.4, 118.5, 112.2, 94.7, 22.3; IR
(neat) 1632, 1513, 1472, 1424, 1328, 1250, 827, 774, 744 cmÀ1; HRMS
calcd for C14H13N2 [M + H]+ 209.10732, found 209.10644.
2-(2-Methoxyphenyl)pyrazolo[1,5-a]pyridine (4f). The title com-
pound was prepared according to general procedure 4 using using 0.5
mmol of 2k. Purification by column chromatography (CH2Cl2, 100%)
afforded 4f as a light beige powder in (78.9 mg, 70%): Rf = 0.27
1
(CH2Cl2/hexanes, 9/1); mp 55 °C; H NMR (300 MHz, CDCl3) δ
8.50 (d, J = 7.0 Hz, 1H), 8.11 (dd, J = 7.7, 1.5 Hz, 1H), 7.53 (d, J = 8.9 Hz,
1H), 7.40À7.34 (m, 1H), 7.12À7.03 (m, 4H), 6.72 (t, J = 6.8 Hz, 1H),
3.96 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 151.1, 146.8, 130.5, 130.46,
130.41, 129.2, 124.1, 122.6, 121.8, 118.9, 112.6, 112.2, 99.0, 56.4; IR
(neat) 3005, 2934, 1633, 1582, 1519, 1478, 1328, 1272, 11244, 1024,
2-(2-Chlorophenyl)pyrazolo[1,5-a]pyridine (4l). The title compound
was prepared according to general procedure 4 using 0.5 mmol of 2r.
Purification by column chromatography CH2Cl2/hexanes, 95/5)
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ARTICLE
afforded 4l as a yellow powder (72.4 mg, 63%). Characterization data
was consistent with that reported in the literature:16 Rf = 0.79 (CH2Cl2,
100%); 1H NMR (300 MHz, CDCl3) δ 8.51 (d, J = 7.2 Hz, 1H), 7.97 (d,
J = 6.9 Hz, 1H), 7.58À7.49 (m, 2H), 7.39À7.27 (m, 2H), 7.11 (t, J = 7.8
Hz 1H), 7.04 (s, 1H); 6.76 (t, J = 6.9 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 151.8, 141.5, 133.6, 133.1, 132.3, 131.2, 130.2, 129.3, 127.8,
124.2, 119.1, 112.9, 99.0; IR (neat) 3031, 1634, 1518, 1462, 1333, 1048,
724 cmÀ1; HRMS calcd for C13H10ClN2 [M + H]+ 229.0527, found
229.05273.
2-(2-Bromophenyl)pyrazolo[1,5-a]pyridine (4m). The title com-
pound was prepared according to general procedure 4 using 0.5 mmol
of 2s. Purification by column chromatography (CH2Cl2, 100%) afforded
4m as a yellow-brown powder (96.0 mg, 70%). Characterization data
was consistent with that reported in the literature:16 Rf = 0.39 (CH2Cl2/
hexanes, 9/1); mp 45À46 °C; 1H NMR (300 MHz, CDCl3,) δ 8.51 (d,
J = 6.9 Hz, 1H), 7.83 (d, J = 7.2 Hz, 1H), 7.73 (d, J = 8.1 Hz, 1H), 7.58 (d,
J = 8.4 Hz, 1H), 7.43 (t, J = 7.8 Hz, 1H), 7.27 (t, J = 8.1 Hz, 1H), 7.14 (t,
J = 8.1 Hz, 1H), 6.99 (s, 1H), 6.78 (t, J = 6.6 Hz, 1H); 13C NMR (75
MHz, CDCl3) δ 153.5, 141.5, 135.4, 134.5, 132.7, 130.5, 129.3, 128.3,
124.2, 123.3, 119.0, 112.8, 98.8. IR (neat) 3055, 1633, 1519, 1458, 1330,
1024, 755, 737, 726 cmÀ1; HRMS calcd for C13H10BrN2 [M + H]+
273.00219, found 273.00219.
2-(3-Bromophenyl)pyrazolo[1,5-a]pyridine (4n). The title compound
was prepared according to General Procedure 4 using 0.5 mmol of 2u.
Purification by column chromatography (hexanes/EtOAc, 1:1) afforded
4n as a yellow-brown powder (81.5 mg, 60%): Rf = 0.63 (CH2Cl2/
hexanes, 9/1); mp 126 °C; 1H NMR (300 MHz, CDCl3,) δ 8.46 (d, J =
7.0 Hz, 1H), 8.14 (s, 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.52À7.48 (m, 2H),
7.31 (t, J = 7.9 Hz, 1H), 7.10 (t, J = 7.8 Hz, 1H), 6.76À6.72 (m, 2H); 13C
NMR (75 MHz, CDCl3) δ 152.8, 142.5, 136.2, 132.1, 131.1, 130.2,
129.3, 125.8, 124.5, 123.8, 118.9, 113.0, 94.8; IR (neat) 3045, 1633,
1519, 1465, 1330, 1068, 772, cmÀ1. HRMS calcd for C13H10BrN2 [M +
H]+ 273.00219, found 273.00234.
δ 8.51 (d, J = 7.2 Hz, 1H), 7.96À7.92 (m, 3H), 7.50À7.38 (m, 3H), 7.69
(s, 1H), 6.83 (d, J = 7.4 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 156.1,
140.8, 132.7, 130.2, 130.1, 129.8, 127.5, 125.3, 118.4, 112.5, 107.7, 97.7;
IR (neat) 3048, 2229, 1523, 1476, 1455, 1431, 1258, 753, 718 cmÀ1
HRMS calcd for C14H10N3 [M + H]+ 220.08692, found 220.08705.
;
3/6-Methyl-2-phenylpyrazolo[1,5-a]pyridine (5b). The title com-
pound was prepared according to general procedure 4 using 1.0 mmol
of 1c. Purification by column chromatography (CH2Cl2/hexanes, 9/1)
afforded 5b a beige powder (45 mg, 77%, inseparable mixture of prod-
ucts). Characterization data was consistent with that reported in the
literature:16 Rf = 0.43 (CH2Cl2, 100%); mp 121À129 °C; 1H NMR (300
MHz, CDCl3) δ 8.29 (s, 1H), 7.98 (d, J = 7.5 Hz, 2H), 7.52À7.34 (m,
4H), 6.94 (d, J = 8.4 Hz, 1H), 6.75 (s, 1H); 13C NMR (75 MHz, CDCl3)
δ 153.7, 143.7, 141.2, 134.4, 129.6, 129.0, 127.4, 123.2, 122.4, 118.0,
112.7, 94.1, 93.5, 18.8; IR (neat) 1507, 1438, 1318, 1027, 809, 761, 691 cmÀ1
;
HRMS calcd for C14H13N2 [M + H]+ 209.10732, found 209.10685.
3/6-Chloro-2-phenylpyrazolo[1,5-a]pyridine (5c). The title com-
pound was prepared according to general procedure 4 using 1.0 mmol
of 1d. Purification by column chromatography (CH2Cl2/hexanes, 9/1)
afforded 5c as a beige powder (45 mg, 77%): Rf = 0.43 (CH2Cl2, 100%);
mp 121À129 °C; 1H NMR (major, 300 MHz, CDCl3) δ 9.42 (m, 1H),
9.22À9.20 (m, 2H), 8.15 (m, 4H), 8.10À8.04 (m, 7H), 7.70À7.65 (m,
3H), 7.58À7.46 (m, 18H), 7.08À6.99 (m, 6H); 13C NMR (major, 75
MHz, CDCl3) δ 154.7, 141.6, 133.5, 129.7, 127.9, 127.4, 124.6, 123.4,
111.9, 94.9; IR (neat) 3069, 3030, 1630, 1533, 745 cmÀ1; HRMS calcd
for C13H10ClN2 [M + H]+ 229.05270, found 229.05282.
2-Phenylpyrazolo[1,5-a]isoquinoline (5d). The title compound was
prepared according to General Procedure 4 using 1.0 mmol of 1e.
Purification by chromatography (CH2Cl2/hexanes, 9/1) afforded 5d as
a beige powder (73.7 mg, 60%). Characterization data was consistent
with that reported in the literature:16 Rf = 0.84 (CH2Cl2, 100%); mp
117 °C; 1H NMR (300 MHz, CDCl3) δ 8.27 (d, J = 6.9 Hz, 1H), 8.12 (d,
J = 7.8 Hz, 1H), 8.03 (d, J = 6.3 Hz, 2H), 7.65 (d, J = 8.1 Hz, 1H),
7.62À7.47 (m, 4H), 7.44À7.37 (m, 1H), 7.29 (s, 1H), 6.98 (d, 1H); 13C
NMR (75 MHz, CDCl3) δ 153.9, 140.7, 134.0, 129.7, 129.2, 128.8,
128.5, 128.1, 127.2, 125.3, 124.6, 113.0, 95.4. IR (neat) 1537, 1460,
1360, 792, 756, 695 cmÀ1; HRMS calcd for C17H13N2 [M + H]+
245.10732, found 245.1067.
2-Phenylpyrazolo[1,5-a]quinoline (5e). The title compound was
prepared according to General Procedure 4 using 1.0 mmol of 1f.
Purification by column chromatography (CH2Cl2/hexanes, 9/1) af-
forded 5e a yellow powder (110.2 mg, 90%). Characterization data was
consistent with that reported in the literature:16 Rf = 0.81 (CH2Cl2,
100%); mp 92À95 °C; 1H NMR (300 MHz, CDCl3) δ 8.70 (d, J = 8.7
Hz, 1H), 8.07 (d, J = 8.1 Hz, 2H), 7.75 (m, 2H), 7.52À7.37 (m, 4H),
6.90 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 153.7, 140.4, 135.8, 134.4,
130.2, 129.6, 129.2, 129.1, 128.2, 125.5, 124.0, 117.5, 116.4, 97.6; IR
(neat) 1732, 1603, 1454, 1392, 1812, 743, 679 cmÀ1; HRMS calcd for
C17H13N2 [M + H]+ 245.10732, found 245.10727.
(E)-Ethyl 2-(Pyrazolo[1,5-a]pyridin-2-yl)acrylate (4o). The title
compound was prepared according to general procedure 4 using 0.4
mmol of 2v. Purification by column chromatography (CH2Cl2/hexanes,
9/1) afforded 4o a light brown oil (42.1 mg, 49% yield). Characteriza-
tion data was consistent with that reported in the literature:16 Rf = 0.26
(CH2Cl2/hexanes, 95/5); 1H NMR (300 MHz, CDCl3) δ 8.41 (d, J =
7.1 Hz, 1H), 7.79 (d, J = 16.1 Hz, 1H), 7.50 (d, J = 8.9 Hz, 1H), 7.12 (d,
J = 7.0 Hz, 1H), 6.78 (t, J = 6.9 Hz, 1H), 6.67 (m, 2H), 4.28 (q, J = 7.1 Hz,
2H), 1.34 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 167.6,
150.3, 142.1, 137.2, 129.3, 124.6, 122.1, 119.2, 113.7, 97.4, 61.4, 15.1; IR
(neat) 2980, 1711, 1650, 1634, 1299, 1269, 1173, 1034, 979 cmÀ1
;
HRMS calcd for C12H13N2O2 [M + H]+ 217.09715, found 217.09671.
2-(2-Phenylcyclopropyl)pyrazolo[1,5-a]pyridine (4p). The title
compound was prepared according to General Procedure 4 using
0.5 mmol of 2w. Purification by column chromatography (CH2Cl2/
hexanes, 9/1) afforded 4p as a light brown powder (73 mg, 62%).
Characterization data was consistent with that reported in the litera-
7-Methoxy-2-phenylpyrazolo[1,5-a]quinoline (5f). The title com-
pound was prepared according to general procedure 4 using 0.3244
mmol of 1g. Purification by chromatography (CH2Cl2/hexanes, 1:1)
afforded 5f as a yellow powder (30.3 mg, 69%): Rf = 0.65 (CH2Cl2/
1
ture:16 Rf = 0.26 (CH2Cl2/hexanes, 95/5); mp 53À55 °C; H NMR
(300 MHz, CDCl3) δ 8.371 (d, J = 7.5 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H),
7.34À7.29 (m, 2H), 7.22À7.17 (m, 3H), 7.04 (t, J = 7.8 Hz, 1H), 6.65
(t, J = 6.9 Hz, 1H), 6.28 (s, 1H), 2.49À2.36 (m, 2H), 1.69À1.62 (m,
1H), 1.55À1.48 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 157.6, 143.0,
142.0, 129.2, 129.0, 126.7, 126.6, 124.1, 118.1, 111.7, 94.4, 28.4, 22.6,
19.3. IR (neat) 3027, 1724, 1632, 1520, 1493, 745, 695 cmÀ1; HRMS
calcd for C16H15N2 [M + H]+ 235.12297, found 235.12373.
1
hexanes, 1:1); mp 98À100 C; H NMR (300 MHz, CDCl3) δ 8.61
(d, J = 9.1 Hz, 1H), 8.06 (d, J = 7.7 Hz, 2H), 7.45 (m, 3H), 7.35À7.27
(m, 3H), 7.15 (m, 1H), 6.88 (s, 1H), 3.93 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 157.4, 153.2, 139.4. 134.4. 130.6, 129.5, 129.0, 127.1, 125.0,
119.3, 117.94, 117.93, 110.2, 97.2, 56.5; IR (neat) 3372, 2935, 1728,
1619, 1563, 1167, 760 cmÀ1; HRMS calcd for C18H15N2O [M + H]+
275.11789, found 275.11824.
2-Phenylpyrazolo[1,5-a]pyridine-5-carbonitrile (5a). The title com-
pound was prepared according to general procedure 4 using 1.0 mmol of
1b. Purification by column chromatography (CH2Cl2/hexanes, 95/5)
affored 5a as a yellow powder (67.4 mg, 62%). Characterization data
was consistent with that reported in the literature:16 Rf = 0.76
(CH2Cl2, 100%); mp 186À189 °C; 1H NMR (300 MHz, CDCl3)
2-Phenylpyrazolo[1,5-a]pyrazine (5g). The title compound was
prepared according to General Procedure 4 using 0.5 mmol of 1h. Puri-
fication by column chromatography (CH2Cl2/hexanes, 9/1) afforded
5g as a white powder (81.5 mg, 60%): Rf = 0.63 (CH2Cl2/hexanes, 1:1);
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ARTICLE
mp 142 °C; 1H NMR (300 MHz, CDCl3) δ 9.04 (s, 1H), 8.39 (d, J =
4.7 Hz, 1H), 7.98 (d, J = 7.4 Hz, 2H), 7.86 (d, J = 4.7 Hz, 1H), 7.51À7.39
(m, 3H), 7.05 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 154.9, 145.3,
138.0, 133.0, 130.1, 129.9, 129.8, 129.4, 128.2, 127.5, 122.5, 96.1. IR
(neat) 3127, 3020, 1527, 1469, 1421, 1331, 1233, 1080 cmÀ1; HRMS
calcd for C12H10N3 [M + H]+ 196.08692, found 196.08726.
114.7, 112.3, 94.5, 21.4; IR (neat) 3085, 2972, 1631, 1518, 1245, 1014,
893, 734 cmÀ1; HRMS calcd for C10H11N2 [M + H]+ 159.09167, found
159.09142.
2-tert-Butylpyrazolo[1,5-a]pyridine (10d). The title compound was
prepared according to general procedure 5 using 0.5 mmol of the alkyne.
Purfication by column chromatography (CH2Cl2/hexanes, 95/5) af-
forded 10d as a light brown oil (55.3 mg, 64%): Rf = 0.75 (CH2Cl2,
100%); 1H NMR (400 MHz, CDCl3) δ 8.42 (d, J = 7.0 Hz, 1H), 7.42 (d,
J = 8.9 Hz, 1H), 7.04À7.00 (m, 1H), 6.65 (t, J = 6.8, Hz, 1H), 6.35 (s,
1H), 1.44 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 164.6, 140.4, 128.0,
122.5, 117.1, 110.3, 92.5, 32.0, 30.4; IR (neat) 3078, 2958, 2864, 1632,
1519, 1492, 1327, 1236, 770 cmÀ1; HRMS calcd for C11H15N2 [M + H]+
175.12297, found 175.12277.
2-(E)-Styryl-N-benzoyliminopyridinium Ylide (3). To a microwave
vial with a stir bar was added the 1a (0.6 mmol, 1.5 equiv), CuBr2 (0.04
mmol, 10 mol %), and crushed dry K2CO3 (0.8 mmol, 2 equiv). The vial
was then sealed with a septum and purged with argon for 5 min. To a
separate vial was added 2a (0.4 mmol, 1 equiv). The iodide was diluted in
PhCl (0.5 mL) and added to the reaction vessel via syringe. The vial and
syringe were then rinsed three times with PhCl (0.5 mL) bringing the
total reaction volume to 2 mL. The reaction was stirred vigorously for 16
h at 125 °C. Following cooling, 2 mL of CH2Cl2/MeOH (9:1) was
added, and the solution was filtered though a silica/Celite pad. The pad
was then rinsed with 15 mL of CH2Cl2/MeOH (9:1). The combined
solution was concentrated and the crude mixture was purified via
column chromatography (CH2Cl2/MeOH, 95/5) to afford 3 as a
cream-colored solid (98.2 mg, 81%). Characterization data was consis-
tent with that reported in the literature:14f Rf = 0.26 (CH2Cl2/MeOH,
95/5); mp 199À201 °C; 1H NMR (300 MHz, CDCl3) δ 8.59 (d, J = 6.9
Hz, 1H), 8.25 (d, J = 7.0 H, 2H), 7.99 (d, J = 8.2 Hz, 1H), 7.85 (t, J = 8.2
H, 1H), 7.78 (d, J = 16.6 Hz, 1H), 7.52À7.41 (m, 7H), 7.36À7.34 (m,
3H); 13C NMR (75 MHz, CDCl3) δ 151.9, 146.2, 140.3, 137.7, 136.0,
131.0, 130.9, 129.8, 129.3, 129.0, 128.8, 128.7, 128.4, 124.1, 124.0, 119.4;
IR (neat) 3054, 1612, 1590, 1552, 1483, 1173, 965 cmÀ1; HRMS calcd
for C20H17N2O (M + H)+ 301.13354, found 301.13502.
General Procedure 5: Synthesis of 2-Substituted Pyrazolo-
[1,5-a]pyridines from Alkynes. To a 3 mL conical microwave vial
equipped with a spin vane was added pyridinium ylide (1.5 mmol, 3
equiv). In a glovebox were added P(4-MeOPh)3 (0.15 equiv), PdBr2
(0.05 equiv), and AgOBz (2.0 mmol, 4 equiv), and the microwave vial
was crimped shut. The alkyne derivative (0.5 mmol, 1 equiv) was
dissolved in 1,4-dioxane (0.5 mL) and added via syringe. The syringe was
rinsed three times with 0.5 mL of dioxane to reach a final volume of
2 mL. The solution was heated to 125 °C with fast stirring. Within 5 min,
a color change was observed. The mixture was stirred for 16 h and then
cooled to room temperature. Dichloromethane was added, and the
precipitate was filtered on a cotton plug and washed with CH2Cl2.
Saturated Na2CO3 was added, and the organic phase was extracted with
CH2Cl2. The solution was dried with Na2SO4 and concentrated under
reduced pressure and purified via column chromatography to afford the
title compounds.
2-Cyclohexenylpyrazolo[1,5-a]pyridine (10b). The title compound
was prepared according to general procedure 5 using 0.5 mmol of the
alkyne. Purfication by column chromatography (CH2Cl2/hexanes, 1/1)
afforded 10b as a light brown powder (84.2 mg, 85%): Rf = 0.43
(CH2Cl2/hexanes, 1/1); mp 44À45 °C; 1H NMR (300 MHz, CDCl3) δ
8.36 (d, J = 7.0 Hz, 1H), 7.42 (d, J = 9 Hz, 1H), 7.00À6.95 (m, 1H),
6.63À6.52 (m, 2H), 6.44 (s, 1H), 2.52À2.60 (m, 2H), 2.21À2.20 (m,
2H), 1.81À1.63 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 155.5, 140.9,
130.2, 128.2, 126.6, 122.9, 117.4, 110.9, 92.4, 26.1, 25.5, 22.6, 22.1; IR
(neat) 3075, 2922, 2854, 1629, 1516, 1488, 1327, 1252, 1138, 918,
767 cmÀ1; HRMS calcd for C13H15N2 [M + H]+ 199.12297, found
199.12269.
2-(Prop-1-en-2-yl)pyrazolo[1,5-a]pyridine (10c). The title com-
pound was prepared according to general procedure 5 using 0.5 mmol
of the alkyne. Purification by column chromatography (CH2Cl2/
hexanes, 7/3) gave 10c as a light brown oil (22.7 mg, 29%): Rf = 0.63
(CH2Cl2/hexanes, 7/3); 1H NMR (400 MHz, CDCl3) δ 8.43 (dd, J =
7.0, 0.9 Hz, 1H), 7.46 (d, J = 8.9 Hz, 1H), 7.08À7.04 (m, 1H), 6.70 (td, J
= 6.9, 1.2 Hz, 1H), 6.59 (s, 1H), 5.78 (s, 1H), 5.23 (s, 1H), 2.26 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 155.6, 141.9, 137.7, 129.2, 124.1, 118.6,
2-Hexylpyrazolo[1,5-a]pyridine (10e). The title compound was
prepared according to general procedure 5 using 0.5 mmol of the
alkyne. Purification by column chromatography (CH2Cl2/hexanes, 95/
5) afforded 10e as a light brown oil (39.3 mg, 50%): Rf = 0.73 (CH2Cl2,
100%); 1H NMR (300 MHz, CDCl3) δ 8.37 (d, J = 7.0 Hz, 1H), 7.41 (d,
J = 8.9 Hz, 1H), 7.04 (t, J = 7.8 Hz, 1H), 6.65 (t, J = 6.9 Hz, 1H), 6.29
(s, 1H), 2.82 (m, 2H), 1.74 (q, J = 7.6 Hz, 2H), 1.41À1.31 (m, 6H), 0.88
(t, J = 6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 157.4, 141.8, 129.0,
123.9, 118.2, 111.5, 95.9, 32.5, 30.6, 30.0, 29.5, 23.5, 14.9; IR (neat)
3081, 2925, 2855, 1634, 1520, 1488, 1328, 1253, 1142, 1021, 765 cmÀ1
;
HRMS calcd for C13H19N2 [M + H]+ 203.15428, found 203.15410.
2-Butylpyrazolo[1,5-a]pyridine (10f). The title compound was pre-
pared according to General Procedure 5 using 0.366 mmol of the alkyne.
The product was purified by column chromatography (CH2Cl2/hex-
anes, 95/5) to give a light brown oil (34.9 mg, 55%): Rf = 0.69 (CH2Cl2,
100%); 1H NMR (300 MHz, CDCl3) δ 8.38 (d, J = 7.0 Hz, 1H), 7.41
(dd, J = 8.9, 0.8 Hz, 1H), 7.04 (d, J = 7.3 Hz, 1H), 6.65 (t, J = 6.9 Hz, 1H),
6.29 (s, 1H), 2.83 (t, J = 7.7 Hz, 2H), 1.75 (quintet, J = 7.5 Hz, 2H), 1.43
(sextet, J = 7.4 Hz, 2H), 0.96 (t, J = 7.3 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 157.3, 141.8, 129.0, 123.9, 118.2, 111.5, 95.9, 32.8, 29.1, 23.4,
14.8; IR (neat) 3072, 2955, 1635, 1520, 1474, 1329, 1254, 1238, 1144,
1023, 767 cmÀ1; HRMS calcd for C11H15N2 [M + H]+ 175.12297,
found 175.12282.
Methyl 9-(Pyrazolo[1,5-a]pyridin-2-yl)nonanoate (10g). The title
compound was prepared according to general procedure 5 using 0.475
mmol of the alkyne. Purification by column chromatography (CH2Cl2,
100%) afforded 10g as a yellow oil (75.9 mg, 54%): Rf = 0.63 (CH2Cl2,
100%); 1H NMR (300 MHz, CDCl3) δ 8.37 (dd, J = 7.0, 0.9 Hz, 1H),
7.42 (dt, J = 8.9, 1.1 Hz, 1H), 7.04 (ddd, J = 8.9, 6.7, 1.1 Hz, 1H), 6.65
(td, J = 6.9, 1.3 Hz, 1H), 6.28 (s, 1H), 3.67 (s, 3H), 2.81 (t, J = 7.7 Hz,
2H), 2.30 (t, J = 7.5 Hz, 2H), 1.77À1.70 (m, 2H), 1.67À1.60 (m, 2H),
1.42À1.31 (m, 10H); 13C NMR (75 MHz, CDCl3) δ 175.1, 157.3,
141.8, 129.0, 123.9, 118.2, 111.5, 95.9, 52.3, 35.0, 30.6, 30.2, 30.1, 30.0,
29.9, 29.4, 25.8; IR (neat) 2926, 2853, 1734, 1634, 1520, 1435, 1253,
1024, 737 cmÀ1; HRMS calcd for C17H24N2NaO2 [M + Na]+
311.17354, found 311.173.
2-(2-(Benzyloxy)propan-2-yl)pyrazolo[1,5-a]pyridine (10h). The ti-
tle compound was prepared according to general procedure 5 using
0.258 mmol of the alkyne. Purification by column chromatography
(CH2Cl2, 100%) afforded 10h as a yellow oil (55.0 mg, 80%): Rf = 0.63
(CH2Cl2, 100%); 1H NMR (300 MHz, CDCl3) δ 8.46 (dt, J = 7.0, 0.9
Hz, 1H), 7.49 (dt, J = 8.9, 1.1 Hz, 1H), 7.37À7.25 (m, 5H), 7.08 (ddd,
J = 8.9, 6.7, 1.1 Hz, 1H), 6.71 (td, J = 6.9, 1.3 Hz, 1H), 6.58 (d, J = 0.8 Hz,
1H), 4.37 (s, 2H), 1.78 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 160.7,
141.9, 140.3, 129.4, 129.1, 128.3, 128.0, 124.1, 118.8, 112.1, 95.2, 75.6,
66.4, 28.5; IR (neat) 3029, 2978, 2932, 2862, 1634, 1520, 1328, 1156,
1057, 776; HRMS calcd for C17H19N2O [M + H]+ 267.14906, found
267.14919.
2-Cyclohexenylpyrazolo[5,1-a]isoquinoline (11a). The title com-
pound was prepared according to general procedure 5 using ylide 1c and
0.25 mmol of the alkyne. Purification by column chromatography
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ARTICLE
(CH2Cl2, 100%) afforded 11a as a yellow powder (44.5 mg, 72%):
Rf = 0.83 (CH2Cl2, 100%); mp 87À88 °C; 1H NMR (300 MHz, CDCl3)
δ 8.19 (d, J = 7.4 Hz, 1H), 8.08À8.06 (m, 1H), 7.71À7.68 (m, 1H), 7.55
(m, 2H), 7.01 (s, 1H), 6.92 (d, J = 7.4 Hz, 1H), 6.60 (m, 1H), 2.63À2.59
(m, 2H), 2.32À2.26 (m, 2H), 1.88À1.71 (m, 4H); 13C NMR (75 MHz,
CDCl3) δ 155.9, 139.9, 131.2, 129.7, 128.6, 128.3, 128.0, 127.4, 127.2,
125.3, 124.5, 112.2, 94.3, 27.0, 26.5, 23.5, 23.1; IR (neat) 2924, 2856,
1634, 1537, 1477, 1368, 1033, 754 cmÀ1; HRMS calcd for C17H17N2
[M + H]+ 249.13862, found 249.13856.
2-Cyclohexenylpyrazolo[1,5-a]pyrazine (11b). The title compound
was prepared according to general procedure 5 using ylide 1f and
0.242 mmol of the alkyne. Purification by column chromatography
(CH2Cl2, 100%) afforded 11b as a yellow oil (34.7 mg, 72%): Rf = 0.52
(CH2Cl2, 100%); 1H NMR (400 MHz, CDCl3) δ 8.59 (dd, J = 8.4, 0.5
Hz, 1H), 7.74À7.72 (m, 1H), 7.65 (m, 1H), 7.43À7.35 (m, 3H),
6.66À6.63 (m, 1H), 6.61 (s, 1H), 2.67À2.63 (m, 2H), 2.33À2.27 (m,
2H), 1.89À1.82 (m, 2H), 1.78À1.72 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 155.8, 130.0, 129.0, 127.2, 125.2, 117.4, 116.3, 95.4, 27.1, 26.5,
23.6, 23.2; IR (neat) 2928, 2856, 1613, 1482, 1386, 1033, 805,
739 cmÀ1; HRMS calcd for C17H17N2 [M + H]+ 249.13949, found
249.13862.
Purification by column chromatography (CH2Cl2, 100%) afforded 12 as
a tan powder (42.4 mg, 29%): Rf = 0.61 (CH2Cl2, 100%); mp 86À88 °C;
1H NMR (300 MHz, CDCl3) δ 8.43 (d, J = 7.0 Hz, 1H), 8.31 (d, J = 7.8
Hz, 2H), 7.98 (d, J = 7.7 Hz, 2H), 7.73À7.68 (m, 1H), 7.58 (t, J = 7.7 Hz,
2H), 7.46À7.34 (m, 4H), 7.12 (m, 1H), 6.79 (t, J = 6.9 Hz, 1H); 13C
NMR (75 MHz, CDCl3) δ 165.2, 144.4, 134.8, 134.2, 132.4, 131.3,
129.7, 129.65, 129.57, 129.4, 128.2, 124.0, 122.9, 117.3, 117.2, 113.0; IR
(neat) 3061, 1741. 1639, 1526, 1474, 1237, 1087, 1022, 741 cmÀ1
HRMS calcd for C20H15N2O2 [M + H]+ 315.11242, found 315.1128.
;
2-Phenylpyrazolo[1,5-a]pyridin-3-yl Acetate (14a). Prepared ac-
cording to general procedure 4 using 0.5 mmol of ylide 13a in the
absence of iodide and alkyne. Purification by column chromatography
(CH2Cl2, 100%) afforded 14a as a tan powder (61.8 mg, 49%): Rf = 0.63
(CH2Cl2, 100%); mp 66À67 °C; 1H NMR (300 MHz, CDCl3) δ 8.38
(d, J = 7.0 Hz, 1H), 7.95À7.92 (m, 2H), 7.51À7.45 (m, 2H), 7.43À7.37
(m, 1H), 7.32 (d, J = 9.0 Hz, 1H), 7.10 (ddd, J = 8.9, 6.7, 0.7 Hz, 1H), 6.75
(td, J=6.9, 1.3Hz, 1H), 2.42(s, 3H);13CNMR(75MHz, CDCl3) δ169.6,
144.2, 134.0, 132.4, 129.5, 129.4, 128.2, 124.0, 122.9, 117.0, 112.9; IR (neat)
3041, 2932, 1762, 1638, 1472, 1348, 1190, 1077, 740 cmÀ1; HRMS calcd
for C15H13N2O2 [M + H]+ 253.09712, found 253.09715.
2-(3,5-(Trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-3-yl Acetate
(14b). Prepared according to general procedure 4 using 0.5 mmol of
ylide 13b in absence of iodide and alkyne. Purification by column
chromatography (CH2Cl2, 100%) afforded 14b as a beige oil (31.8 mg,
19%): Rf = 0.67 (CH2Cl2, 100%); 1H NMR (400 MHz, CDCl3) δ 8.45
(s, 2H), 8.41 (dd, J = 7.1, 1.0 Hz, 1H), 7.90 (s, 1H), 7.40 (dt, J = 9.0, 1.2
Hz, 1H), 7.19 (ddd, J = 9.0, 6.7, 1.0 Hz, 1H), 6.87 (td, J = 6.9, 1.3 Hz,
1H), 2.46 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 169.2, 140.1, 134.6,
134.3, 133.1, 132.6, 129.4, 127.8 (m), 124.6, 124.0 (q, J = 272.8 Hz),
122.0 (m), 117.4, 114.0, 21.4; IR (neat) 3047, 1764, 1360, 1282, 1172,
1121, 896, 747 cmÀ1; HRMS calcd for C17H10F6N2NaO2 [M + Na]+
411.05446, found 411.05387.
2-(4-Methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl Acetate (14c).
Prepared according to general procedure 4 using 0.206 mmol of ylide
13c in the absence of iodide and alkyne. Purification by column
chromatography (CH2Cl2, 100%) afforded 14c as a beige oil (13.2
mg, 23%): Rf = 0.61 (CH2Cl2, 100%); 1H NMR (300 MHz, CDCl3): δ
8.36 (dt, J = 7.0, 1.0 Hz, 1H), 7.89À7.84 (m, 2H), 7.31À7.27 (m, 1H),
7.09 (ddd, J = 9.0, 6.7, 1.0 Hz, 1H), 7.03À6.98 (m, 2H), 6.73 (td, J = 6.9,
1.4 Hz, 1H), 3.87 (s, 3H), 2.42 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
169.6, 160.7, 160.7, 144.1, 134.0, 129.4, 129.3, 124.9, 123.9, 122.4, 116.7,
115.0, 112.6, 56.1, 21.6; IR (neat) 2935, 1763, 1612, 1481, 1247, 1174,
1029, 836, 742 cmÀ1; HRMS calcd for C16H14N2NaO3 [M + Na]+
305.091, found 305.08966.
2-Cyclohexenyl-6- and -4-methylpyrazolo[1,5-a]pyridine (11c).
The title compound was prepared according to general procedure 5
using ylide 1g and 0.25 mmol of the alkyne. Purification by column
chromatography (CH2Cl2, 100%) afforded 11c as an inseparable 4:1
mixture toward the least hindered product (44.5 mg, 72% combined):
1
Rf = 0.83 (CH2Cl2, 100%); mp: 46À47 °C; H NMR (300 MHz,
CDCl3) δ 8.28À8.25 (m), 8.20 (s, 1H), 7.33 (d, J = 9.0 Hz, 1H), 6.89 (d,
J = 9.1 Hz, 1H), 6.59À6.55 (m, 1H), 6.44 (m, 1H), 3.71 (s, 1H),
2.56À2.51 (m, 3H), 2.43 (s, 1H), 2.30À2.21 (m, 6H), 1.84À1.66 (m,
6H); 13C NMR (75 MHz, CDCl3) δ 156.0, 155.8, 142.9, 140.4, 131.3,
128.1, 127.3, 127.1, 127.0, 126.9, 126.8, 122.7, 121.6, 117.1, 112.0, 92.9,
92.2, 67.9, 54.3, 27.1, 26.5, 23.0, 23.1, 19.1, 18.9; IR (neat) 2922, 1642,
1517, 1485, 1435, 1319, 1054, 797 cmÀ1; HRMS calcd for C14H17N2
[M + H]+ 213.13862, found 213.13841.
(2-Cyclohexenylpyrazolo[1,5-a]pyridin-5-yl)(phenyl)methanone (11d).
The title compound was prepared according to general procedure
5 using ylide 1i and 0.241 mmol of the alkyne. Purification by col-
umn chromatography (CH2Cl2, 100%) afforded 11d as a yellow oil
1
(32.8 mg, 45%): Rf = 0.59 (CH2Cl2, 100%); H NMR (400 MHz,
CDCl3) δ 8.48 (dd, J = 7.2, 0.8 Hz, 1H), 7.90 (dd, J = 1.7, 0.8 Hz,
1H), 7.86À7.83 (m, 2H), 7.67À7.63 (m, 1H), 7.56À7.52 (m, 2H),
7.23 (dd, J = 7.2, 1.9 Hz, 1H), 6.70 (s, 1H), 6.65À6.62 (m, 1H),
2.59À2.54 (m, 2H), 2.31À2.26 (m, 2H), 1.87À1.81 (m, 2H), 1.74 (m,
2H); 13C NMR (75 MHz, CDCl3) δ 195.4, 157.6, 140.3, 138.0, 133.5,
132.7, 130.8, 130.6, 129.3, 129.1, 128.4, 122.6, 111.5, 96.7, 27.0, 26.56,
23.4, 23.0; IR (neat) 2927, 1652, 1516, 1319, 1258, 1112, 736,
710; HRMS calcd for C20H18N2NaO [M + Na]+ 325.13133, found
325.13113.
(E)-2-Cyclohexenyl-7-styrylpyrazolo[1,5-a]pyridine (11e). The title
compound was prepared according to general procedure 5 using ylide 3
and 0.25 mmol of the alkyne. Purification by column chromatography
(CH2Cl2, 100%) afforded 11e as a yellow powder (13.9 mg, 21%): Rf =
0.73 (CH2Cl2, 100%); mp 95À98 °C; 1H NMR (300 MHz, CDCl3) δ
7.82 (s, 2H), 7.64À7.60 (m, 2H), 7.41À7.36 (m, 3H), 7.33À7.27 (m,
1H), 7.08À7.03 (m, 1H), 6.97À6.94 (m, 1H), 6.68À6.63 (m, 1H), 6.53
(s, 1H), 2.63À2.56 (m, 2H), 2.30À2.22 (m, 2H), 1.84À1.71 (m, 4H);
13C NMR (75 MHz, CDCl3) δ 154.7, 141.8, 137.3, 136.9, 133.9, 130.5,
128.6, 128.3, 127.1, 126.4, 122.7, 120.1, 115.9, 109.3, 92.8, 26.1, 25.6,
22.6, 22.2; IR (neat) 3057, 2924, 1632, 1522, 1305, 1260, 1080, 782,
717 cmÀ1; HRMS calcd for C21H21N2 [M + H]+ 301.16993, found
301.16961.
’ ASSOCIATED CONTENT
1
Supporting Information. Table S1, H and 13C NMR
S
b
spectra for new compounds, and X-ray data for compounds 4a
and 12. This material is available free of charge via the Internet at
http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: andre.charette@umontreal.ca.
’ ACKNOWLEDGMENT
This work was supported by the Natural Science and En-
gineering Research Council of Canada (NSERC), Merck Frosst
Canada Ltd., Boehringer Ingelheim (Canada), Ltd., the Canada
Research Chairs Program, the Canadian Foundation for Innova-
tion, and the Universitꢀe de Montrꢀeal. J.J.M. is grateful to FQRNT
2-Phenylpyrazolo[1,5-a]pyridin-3-yl Benzoate (12). Prepared ac-
cording to general procedure 4 using ylide 13a and 0.5 mmol of 2a.
8260
dx.doi.org/10.1021/jo201303x |J. Org. Chem. 2011, 76, 8243–8261

The Journal of Organic Chemistry
ARTICLE
for a postgraduate scholarship. We also thank Guillaume Pelletier
for supplying compounds 1f and 2r. We are grateful to Francine
Bꢀelanger-Gariꢀepy and CYLView for X-ray analysis.
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