Direct Alkynylation of 3H-Imidazo[4,5-b]pyridines Using gem-Dibromoalkenes as Alkynes Source

Article abstract of DOI:10.1021/acs.joc.6b00406

C2 direct alkynylation of 3H-imidazo[4,5-b]pyridine derivatives is explored for the first time. Stable and readily available 1,1-dibromo-1-alkenes, electrophilic alkyne precursors, are used as coupling partners. The simple reaction conditions include an inexpensive copper catalyst (CuBr·SMe₂ or Cu(OAc)₂), a phosphine ligand (DPEphos) and a base (LiOtBu) in 1,4-dioxane at 120 °C. This C-H alkynylation method revealed to be compatible with a variety of substitutions on both coupling partners: heteroarenes and gem-dibromoalkenes. This protocol allows the straightforward synthesis of various 2-alkynyl-3H-imidazo[4,5-b]pyridines, a valuable scaffold in drug design.

Full text of DOI:10.1021/acs.joc.6b00406

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Article
Direct alkynylation of 3H-imidazo[4,5-b]pyridines
using gem-dibromoalkenes as alkynes source
Jessy Aziz, Tom Baladi, and Sandrine PIGUEL
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00406 • Publication Date (Web): 25 Apr 2016
Downloaded from http://pubs.acs.org on April 28, 2016
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Direct alkynylation of 3H-imidazo[4,5-b]pyridines using gem-
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dibromoalkenes as alkynes source
Jessy Aziz,†, § Tom Baladi,†, § Sandrine Piguel*, ‡
† Institut Curie, PSL Research University, CNRS, INSERM, UMR9187ꢀU1196,
Fꢀ91405, Orsay, France
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‡ Institut Curie, Université Paris Sud, Université ParisꢀSaclay, Fꢀ91405, Orsay, France
Abstract: C2 direct alkynylation of 3Hꢀimidazo[4,5ꢀb]pyridine derivatives is explored
for the first time. Stable and readilyꢀavailable 1,1ꢀdibromoꢀ1ꢀalkenes, electrophilic alkyne
precursors, are used as coupling partners. The simple reaction conditions include an
inexpensive copper catalyst (CuBr.SMe2 or Cu(OAc)2), a phosphine ligand (DPEphos)
and a base (LiOtBu) in 1,4ꢀdioxane at 120 °C. This C – H alkynylation method revealed
to be compatible with a variety of substitutions on both coupling partners: heteroarenes
and gemꢀdibromoalkenes. This protocol allows the straightforward synthesis of various 2ꢀ
alkynylꢀ3Hꢀimidazo[4,5ꢀb]pyridine, a valuable scaffold in drugꢀdesign.
INTRODUCTION
Transitionꢀmetal catalyzed direct C – H functionalization has become a useful tool in
modern organic chemistry acknowledging today’s need for complex molecules.1 It allows
access to a diversity of functional structures in an effective and straightforward manner.
Nonetheless, heterocycles remain a challenge in organic synthesis due to their lack of
reactivity and regioselectivity issues.2 In fact, heteroarenes with strongly coordinating
atoms, like nitrogen and sulfur, tend to poison the transitionꢀmetal catalyst or activate an
undesired position. Despite these limitations, direct functionalization of heterocycles
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engages a wide part of the recent studies considering that they are commonly present in
natural and synthetic compounds.3 Many reports described direct C – H arylations,4
alkenylations5 and alkylations5a,6 of heterocyclic compounds. Compared to those,
protocols for the direct alkynylation of an sp2–hybridized heteroaryl carbon are still
scarce. Indeed, the lack of reactivity of alkynes, more electronꢀdeficient than the
corresponding alkenes, makes it harder to couple them with heteroarenes. As a
consequence, terminal alkyne precursors have been developed to facilitate acetylene
exchange.7 Halogenoalkynes,8 hypervalent alkynyliodoniums,9 acetylenic sulfones,10
copper acetylides11 and α,βꢀynoic acids12 allowed the generation of more activated alkyne
moieties thus broadening the applications of direct alkynylation reactions to heterocycles.
Among these alternatives, gemꢀdihaloalkenes emerged as more efficient coupling partners
than the corresponding monohalogenated alkynes along with being inexpensive and
readilyꢀavailable.13 Indeed, the two geminal halogen atoms on the alkenyl carbon enhance
the reactivity for the oxidative addition of metal complexes thus facilitating crossꢀ
coupling reactions.14 All of the above alkyne precursors were used for the C – H
alkynylation of indole, pyrrole, oxazole and thiazole derivatives. To our knowledge, no
direct C2 alkynylation method was described for the 3Hꢀimidazo[4,5ꢀb]pyridine scaffold,
in which we were particularly interested as a part of a medicinal chemistry program. This
heteroarene, a purine isostere, has been increasingly studied in drug design and
development. For example, it can be found in candidates targeting cancer,15
hypercholesterolemia,16 infections17 and hypertension.18
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From a chemical point of view, only one method explored the synthesis of C2ꢀalkynylated
3Hꢀimidazo[4,5ꢀb]pyridines (Scheme 1, equation 1).19 It consisted of a copperꢀfree
Sonogashira coupling between C2ꢀhalogenatedꢀ3Hꢀimidazo[4,5ꢀb]pyridine and terminal
alkynes. Nevertheless, this process was limited to N3ꢀcyclopentylꢀ2ꢀhalogenꢀ3Hꢀ
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imidazo[4,5ꢀb]pyridines and the authors did not mention the influence of other protecting
groups on the coupling outcome. In this paper, we disclose our recent findings on the
direct alkynylation of N3ꢀprotectedꢀ3Hꢀimidazo[4,5ꢀb]pyridine derivatives using 1,1ꢀ
dibromoꢀ1ꢀalkenes as alkyne precursors (Scheme 1, equation 2).
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Scheme 1. Synthetic pathways to C2-alkynylated-3H-imidazo[4,5-b]pyridines
RESULTS AND DISCUSSION
We initiated our study by testing different N3ꢀprotectedꢀ6ꢀbromoꢀ3Hꢀimidazo[4,5ꢀ
b]pyridines in order to determine the most suitable protecting group for this coupling. For
this purpose, the conditions previously developed in our group for the C – H alkynylation
of azoles were applied (Table 1).13a It was clearly noticed that the pꢀmethoxybenzyl
(PMB) protection gave the best results for the desired alkynyl compounds. In fact,
coupling N3ꢀbenzylꢀ (Bn) and N3ꢀPMBꢀ3Hꢀimidazo[4,5ꢀb]pyridine respectively with 1,1ꢀ
dibromostyrene 4a afforded 5a and 6a with similar yields. However, using 4b as coupling
partner gave 5b in only 42 % yield and 6b in a good 60 % yield. The 2ꢀ
methoxyethoxymethyl ether (MEM) protecting group was the least effective providing 7a
and 7b in 19 and 33 % yield respectively under the standard conditions. Therefore, we
decided to select PMB as a protecting group. Moreover, previous reports demonstrated
that PMBꢀprotected azoles can be easily deprotected under acidic conditions.20
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Table 1. Direct alkynylation of different N3-protected-6-bromo-3H-imidazo[4,5-
b]pyridines
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R =
Protecting Group
Yield(b)
5a 66 %
6a 65 %
7a 19 %
5b 42 %
6b 60 %
7b 33 %
Bn
Ph
PMB
MEM
Bn
PMB
MEM
2ꢀnaphthyl
a Unless otherwise noted, reaction conditions are: N3ꢀprotectedꢀ6ꢀbromoꢀ3Hꢀimidazo[4,5ꢀ
b]pyridine (0.35 mmol), 1,1ꢀdibromoꢀ1ꢀalkene (2 equiv), CuBr.SMe2 (10 mol%),
DPEphos (20 mol%), LiOtBu (6 equiv), 1,4ꢀdioxane (2 mL) at 120 °C for 4 hours.
b
Isolated yields.
Subsequently, we performed optimization studies using 2 and 4a as benchmark partners
(Table 2). The copper catalyst was first modified. While copper iodide (CuI) and copper
sulfate (CuSO4) afforded the desired product in low yields (Entries 2ꢀ3), copper acetate
(Cu(OAc)2) gave 6a in 64% yield similar to the initial copper bromide in dimethyl sulfide
complex (CuBr.SMe2) (Entries 4 and 1 respectively). The use of palladium as the
transitionꢀmetal catalyst led to no desired product 6a (Entry 5). Next, we turned our
attention to the ligand effect. Several bidentate phosphines with similar steric and
electronic effects as DPEphos were tested (XantPhos, Binap, Dppp) (Entries 6ꢀ8).
However, none of them gave better results. During our study, we noticed that the amount
and the quality of the base played a crucial role in this coupling.21 Compared to the initial
6 equivalents used (Entry 1), 4 equivalents of LiOtBu led to only 53 % yield of isolated
6a (Entry 9) whereas 8 equivalents afforded 6a without a noticeable progress in the final
outcome (Entry 10). The solvent effect was also evaluated (Entries 1, 11, 12) and 1,4ꢀ
dioxane delivered 6a in the highest 65 % yield (Entry 1).
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Table 2. Optimization of the direct coupling between 6-bromo-3H-imidazo[4,5-
b]pyridine 2 and (2,2-dibromovinyl)benzene 4a
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Entry
Catalyst
CuBr.SMe2
CuI
CuSO4.5H2O
Cu(OAc)2
Pd(OAc)2
CuBr.SMe2
CuBr.SMe2
CuBr.SMe2
CuBr.SMe2
CuBr.SMe2
CuBr.SMe2
CuBr.SMe2
CuBr.SMe2
Ligand
DPEphos
DPEphos
DPEphos
DPEphos
DPEphos
XantPhos
(±)Binap
Dppp
DPEphos
DPEphos
DPEphos
DPEphos
DPEphos
Solvent
1,4-dioxane
1,4ꢀdioxane
1,4ꢀdioxane
1,4ꢀdioxane
1,4ꢀdioxane
1,4ꢀdioxane
1,4ꢀdioxane
1,4ꢀdioxane
1,4ꢀdioxane
1,4ꢀdioxane
Toluene
Yield 6a(b)
65%
35%
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31%
64%
0%
59%
30%
45%
53%
69%
9(c)
10(d)
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13(e)
25%
Traces
49%
PhF
1,4ꢀdioxane
a
Unless otherwise noted, reaction conditions are: 6ꢀbromoꢀ3Hꢀimidazo[4,5ꢀb]pyridine
2 (0.35mmol), (2,2ꢀdibromovinyl)benzene 4a (2 equiv), [Cu] (10 mol%), Ligand (20
mol%), LiOtBu (6 equiv), Solvent (2 mL) at 120 °C for 4 hours. Isolated yields. 4
equivalents of LiOtBu were used. 8 equivalents of LiOtBu were used. 5 mol% of
CuBr.SMe2 and 10 mol% of DPEphos were used. DPEphos,
Bis[(diphenylphosphino)phenyl]ether; Dppp, 1,1ꢀbisꢀ(diphenylphosphino)propane;
XantPhos, 4,5ꢀBis(diphenylphosphino)ꢀ9,9ꢀdimethylxanthene; Binap, (2,2'ꢀ
bis(diphenylphosphino)ꢀ1,1'ꢀbinaphthyle.
b
c
d
e
Finally, when decreasing the catalyst loading to 5 mol% of copper, 6a was obtained in a
lower yield (Entry 13). The optimal conditions for the C – H direct alkynylation of 3Hꢀ
imidazo[4,5ꢀb]pyridines with gemꢀdibromoalkenes turned out to be: CuBr.SMe2 (10
mol%), DPEphos (20 mol%) and LiOtBu (6 equiv) in 1,4ꢀdioxane at 120 °C.
Meanwhile, we were interested in generating N3ꢀunprotected imidazo[4,5ꢀb]pyridines.
Therefore, deprotection of N3ꢀPMB alkyne 6a was performed under acidic conditions.
Unfortunately, the desired deprotected compound could not be isolated even though
different acids were tested (hydrochloric, sulfuric and trifluoroacetic acids). Degradation
of compound 6a was observed with the formation of unidentified byꢀproducts. For this
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reason, we turned our attention to MEM as a protecting group. The direct alkynylation
conditions developed in Table 2 led to the formation of compound 7a in only 19 % yield
(Scheme 2). When Cu(OAc)2 was used as catalyst instead of CuBr.SMe2, the isolated
yield of 7a was increased to 46 %. The same improvement was noted for compound 7b
isolated in 77 % yield. The optimized conditions were subsequently applied to a variety
of 1,1ꢀdibromoꢀ1ꢀalkenes 4a-n (Scheme 2). Electronꢀrich and electronꢀdeficient gemꢀ
dibromo olefins reacted with 6ꢀbromoꢀ3Hꢀimidazo[4,5ꢀb]pyridine 3a to provide C2ꢀ
alkynylꢀ3Hꢀimidazo[4,5ꢀb]pyridines in moderate to good yields. 4ꢀphenylꢀ
dibromostyrene gave the coupling product 7c in only 44 % yield. Electronꢀrich
dibromoalkenes (Me, OMe and OTBDMS substitutions) allowed better results furnishing
alkynes 7d-g between 53 to 60 % isolated yields. Sterically hindered dibromoalkenes
were also compatible with the optimized conditions and product 7e was isolated in a 60 %
yield. Compound 7h with mꢀfluorine substituted benzene was obtained with only 36 %
yield. We were pleased to notice that halogen substitutions on the gemꢀdibromoalkenes
were also tolerated, enabling further functionalizations. Indeed, pꢀchloro and mꢀbromo
alkenes reacted successfully with 3Hꢀimidazo[4,5ꢀb]pyridine 3a and afforded the
corresponding coupling products 7i-k in moderate yields. Electronꢀwithdrawing
trifluoromethyl moiety decreased the reactivity of the dibromoalkene and compound 7l
was isolated in only 31 % yield. Alkyne 7m, resulting from the C – H alkynylation of 3a
with 3ꢀ(2,2ꢀdibromoethenyl)thiophene, was obtained in 51 % yield. Unfortunately, the
copperꢀcatalyzed alkynylation conditions were not compatible with a nitrile functional
group. Alkyl gemꢀdibromoalkenes were not reactive and starting material 3a was mainly
recovered. It must be mentioned that CuBr.SMe2 and Cu(OAc)2 gave the same isolated
yields for compounds 7d, 7f, 7h, 7l and CuBr.SMe2 gave better results for compounds 7i,
7k and 7m.22
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Scheme 2. Direct alkynylation between N3-MEM-6-bromo-3H-imidazo[4,5-
b]pyridine 3a and various dibromoalkenes (a), (b)
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7a 19 % / 46 %(c)
7c 44 %
7b 33 % / 77 %(c)
7d 53 %
7e 60 %
7g 55 %
7i 54 %
7f 52 %
7h 36 %
7j 51 %
7k 47 %
7m 51 %
7l 31 %
7n 0 %
a Unless otherwise noted, reaction conditions are: 6ꢀbromoꢀ3Hꢀimidazo[4,5ꢀb]pyridine 3a
(0.35mmol), (2,2ꢀdibromovinyl)benzene 4 (2 equiv), CuBr.SMe2 (10 mol%), DPEphos
(20 mol%), LiOtBu (6 equiv), 1,4ꢀdioxane (2 mL) at 120 °C for 4 hours.b Average
isolated yield after 2 runs. c Cu(OAc)2 (10 mol%) was used as copper catalyst.
Next, the effect of a variety of substitutions on the 3Hꢀimidazo[4,5ꢀb]pyridine scaffold
was evaluated (Scheme 3). When bromine atom at position 6 was replaced by chlorine
atom at position 5, a drop in the reaction yields was observed (8a versus 7b, 8b versus
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7f).When chlorine atom was inserted at position 7 along with bromine at position 6,
compound 8c was isolated with a good 60 % yield while gemꢀdibromoalkene with an
electronꢀdonating methoxy substitution afforded 8d in just 39 % yield. Next, 6ꢀarylꢀ
imidazo[4,5ꢀb]pyridine 3d-f reacted well with 2ꢀnaphthylꢀ1,1ꢀdibromoethenyl giving
alkynes 8e, 8g and 8i in moderate to good yields. However, pꢀmethoxyꢀ1,1ꢀ
dibromostyrene was less reactive towards the C2 alkynylation of 6ꢀarylꢀ3Hꢀimidazo[4,5ꢀ
b]pyridine since compounds 8f, 8h and 8j were obtained in 30, 30 and 35 % yield
respectively. Substitution with electronꢀdeficient 4ꢀpyridyl heterocycle on C6 of the 3Hꢀ
imidazo[4,5ꢀb]pyridine 3g led to alkynes 8k and 8l in satisfying yields. Finally, nonꢀ
substituted 3Hꢀimidazo[4,5ꢀb]pyridine 3h afforded the coupling products 8m and 8n in
moderate yields. As a conclusion, the nature of the substituents on the 3Hꢀimidazo[4,5ꢀ
b]pyridine derivatives and on the gemꢀdibromoalkenes both play a crucial role on the C2
direct alkynylation outcome.
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Scheme 3. Direct alkynylation between various N3-MEM-3H-imidazo[4,5-b]-
pyridines 3 and dibromoalkenes 4(a), (b)
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8a 50 %
8c 60 %
8e 72 %
8b 35 %
8d 39 %
8f 30 %
8i 70 %
8k 62 %(c)
8m 42 %
8j 35 %
8l 59 %
8n 56 %
8g 54 %
8h 30 %
a
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Unless otherwise noted, reaction conditions are: 3Hꢀimidazo[4,5ꢀb]pyridine 3 (0.35mmol), (2,2ꢀ
dibromovinyl)benzene 4 (2 equiv), CuBr.SMe2 (10 mol%), DPEphos (20 mol%), LiOtBu (6 equiv), 1,4ꢀ
dioxane (2 mL) at 120 °C for 4 hours. Average isolated yield after 2 runs. Cu(OAc)2 (10 mol%) was
used as copper catalyst.
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b
c
From a mechanistic point of view, two possible pathways can be envisioned for the direct
alkynylation of 3Hꢀimidazo[4,5ꢀb]pyridines (Scheme 4). In pathway A, the sequence
starts by the coordination of the copper complex I to the nitrogen adjacent to the activable
C – H bond of the 3Hꢀimidazo[4,5ꢀb]pyridine (N1) leading to intermediate II. A previous
report by Fairlamb et al. demonstrated the crucial role of N1 in purine nucleosides
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towards transitionꢀmetal coordination.23 This metalꢀcoordination enhances the acidity and
therefore the reactivity of the C2 – H bond of the heterocycle, as described by Gorelsky.24
Indeed, when our optimized conditions were applied to N3ꢀprotected indole and 7ꢀ
azaindole, no coupling products were isolated.25
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Scheme 4. Proposed mechanism for the direct alkynylation of 3H-imidazo[4,5-
b]pyridines
In the next step, deprotonation in the presence of a base and rearrangement lead to 2ꢀ
cuprioꢀ3Hꢀimidazo[4,5ꢀb]pyridine III.13a This latter can also be obtained according to
pathway B. A ligand exchange between complex I and the base furnishes alkoxide
complex IV as proposed by Hartwig et al.26 Internal deprotonation of 3Hꢀimidazo[4,5ꢀ
b]pyridine via intermediate
V
forms copper complex III.
Meanwhile,
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dehydrobromination of the dibromoalkene 4 leads to the corresponding bromoalkyne
which can form diyne VI by homocoupling. When N3ꢀPMBꢀ3Hꢀimidazo[4,5ꢀb]pyridine 2
reacted with phenylethynyl bromide, product 6a was obtained in 60 % yield following the
reaction conditions described in Table 1. This observation along with the formation of
diyne VI as the main side product in this direct alkynylation reaction confirm the
dehydrobromination of dibromoalkene 4. An oxidative addition of bromoalkyne onto
complex III results in a four coordinated copper(III) intermediate VII. A subsequent
reductive elimination step generates the coupling product with the regeneration of the
catalytic system. Both of the proposed pathways require a large excess of base (6
equivalents) for the deprotonation step of the 3Hꢀimidazo[4,5ꢀb]pyridine as well as for
the dehydrobromination step of the dibromoalkene.
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Finally, some of the N3ꢀMEMꢀ6ꢀbromoꢀ2ꢀalkynylꢀ3Hꢀimidazo[4,5ꢀb]pyridines 7 were
deprotected under acidic conditions. Even though obtained in moderate yields, we
succeeded in synthesizing N3ꢀunprotected 2ꢀalkynylꢀimidazo[4,5ꢀb]pyridines 9 as
illustrated in scheme 5.
Scheme 5. Deprotection of N3-MEM-3H-imidazo[4,5-b]pyridine derivatives
In summary, a copperꢀcatalyzed direct C2 – H alkynylation of 3Hꢀimidazo[4,5ꢀ
b]pyridines has been developed for the first time. To this end, readily available gemꢀ
dibromoalkenes were used as electrophilic alkynylating reagents. The optimized reaction
conditions were compatible with different substituents and protecting groups on the 3Hꢀ
imidazo[4,5ꢀb]pyridine. At the same time, a wide variety of electronꢀrich and electronꢀ
deficient dibromoalkenes reacted successfully with the 3Hꢀimidazo[4,5ꢀb]pyridine
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moiety. This procedure expands the scope of direct alkynylation reactions and represents
an original method for the functionalization of the 3Hꢀimidazo[4,5ꢀb]pyridine scaffold,
recently explored in medicinal chemistry.
9
EXPERIMENTAL SECTION
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General remarks. Commercially available reagents and solvents were used without
further purification. Depending on the supplier and the batch used, LiOtBu had to be reꢀ
purified by sublimation. Yields refer to isolated and purified products. Reactions were
monitored by Thin Layer Chromatography (TLC) carried out on 60Fꢀ254 silica gel plates
and visualized under UV light at 254 and 365 nm. Column chromatography was
performed on a Combiflash Companion using preꢀpacked silica 60 columns. Chemical
1
shifts (δ) of H and 13C NMR are reported in ppm and residual non deuterated solvents
were used as references. Multiplicities are designated by the following abbreviations: s =
singlet, d = doublet, t = triplet, q = quadruplet, bs = broad singlet, m = multiplet. Melting
points were measured with a Stuart SMP30. Highꢀresolution mass spectra (HRMS) were
measured by a TOF spectrometer, using electrospray ionization (ESI) or atmospheric
pressure photoionization (APPI) method.
Typical procedure A for the synthesis of variously substituted 3H-imidazo[4,5-
b]pyridines: To a mixture of substituted 2,3ꢀdiaminopyridine (1 equiv) in
trimethylorthoformate was added dropwise a concentrated solution of HCl (35 %) (2
equiv). The reaction was stirred overnight at room temperature. Subsequently, the
reaction mixture was dissolved in H2O, neutralized by addition of a 3 M NaOH aqueous
solution and extracted with AcOEt. The combined organic layers were dried with
anhydrous MgSO4 and filtered. Evaporation of the solvent under reduced pressure
allowed the desired products with no further purification.
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Preparation of 3-benzyl-6-bromo-3H-imidazo[4,5-b]pyridine (1): 6ꢀbromoꢀ3Hꢀ
imidazo[4,5ꢀb]pyridine a was prepared following procedure A with commercially
available 2,3ꢀdiaminoꢀ5ꢀbromopyridine (12.00 g, 63.82 mmol) in trimethylorthoformate
(200 mL) to give a (12.00 g, 95 %) as a dark grey solid; mp: 223 – 225 °C; 1H NMR (300
MHz, DMSOꢀd6) δ (ppm) 8.47 (s, 1H), 8.41 (d, J = 1.6 Hz, 1H), 8.27 (d, J = 1.2 Hz, 1H);
MS (ES+) m/z (%): 198.0 (100) [M+H]+. Spectroscopic data were in agreement with
those reported in the literature.27
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To a mixture of compound a (6.00 g, 30.30 mmol) in dry DMF (80 mL) at 0 °C under
argon atmosphere was added NaH (a 60 % dispersion in mineral oil) (1.33 g, 33.33 mmol,
1.1 equiv) portionwise. The mixture was left stirring at 0 °C for 30 min under argon inlet
then benzyl bromide (5.70 g, 33.33 mmol, 1.1 equiv) was added dropwise. The reaction
mixture was then allowed to warm up to room temperature and stirred under argon
atmosphere overnight. Subsequently, the DMF was evaporated under reduced pressure
and the resulting residue was taken in H2O and extracted with AcOEt. The combined
organic layers were dried on MgSO4, filtered and concentrated under reduced pressure.
The crude product was purified by column chromatography (Cyclohexane/AcOEt 80/20)
to give 1 as a beige solid (3.40 g, 39 %); mp: 106 – 108 °C; 1H NMR (300 MHz, CDCl3)
δ (ppm) 8.47 (d, J = 1.7 Hz, 1H), 8.21 (d, J = 1.6 Hz, 1H), 8.02 (s, 1H), 7.41 – 7.26 (m,
5H), 5.44 (s, 2H); 13C NMR (75 MHz, CDCl3) δ (ppm) 145.8, 145.5, 145.2, 136.5, 135.5,
130.5, 129.2, 128.6, 127.9, 114.2, 47.4; MS (ES+) m/z (%): 288.0 (100) [M+H]+; HRMS
(ESI) calculated for C13H11N3Br 288.0136 found 288.0150.
Preparation of 6-bromo-3-(p-methoxybenzyl)-3H-imidazo[4,5-b]pyridine (2): To a
mixture of the 6ꢀbromoꢀ3Hꢀimidazo[4,5ꢀb]pyridine a (4.00 g, 20.20 mmol) in dry DMF
(58 mL) at 0 °C under argon atmosphere was added NaH (60% dispersion in mineral oil)
(0.90 g, 22.20 mmol, 1.1 equiv) portionwise. The mixture was left stirring at 0 °C for 30
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min under argon atmosphere then p-methoxybenzyl bromide (0.90 g, 22.20 mmol, 1.1
equiv) was added dropwise. The reaction mixture was then allowed to warm up to RT and
stirred under argon atmosphere overnight. Subsequently, the DMF was evaporated under
reduced pressure and the resulting residue was taken in H2O and extracted with AcOEt.
The combined organic layers were dried on MgSO4, filtered and concentrated under
reduced pressure. The crude product was purified by column chromatography
(Cyclohexane/AcOEt 70/30) to give 2 as a green solid (2.50 g, 39 %); mp: 102 – 104 °C;
1H NMR (300 MHz, CDCl3) δ (ppm) 8.47 (d, J = 1.8 Hz, 1H), 8.20 (d, J = 1.8 Hz, 1H),
7.99 (s, 1H), 7.26 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.5 Hz, 2H), 5.37 (s, 2H), 3.79 (s, 3H);
13C NMR (75 MHz, CDCl3) δ (ppm) 159.7, 145.7, 145.2, 144.9, 136.5, 130.4, 129.4,
127.4, 114.4, 114.0, 55.3, 46.9; MS (ES+) m/z (%): 318.0 (100) [M+H]+, 359.0 (10)
[M+CH3CN+H]+; HRMS (ESI) calculated for C14H13N3OBr 318.0242 found 318.0237.
Typical procedure B for the protection of 3H-imidazo[4,5-b]pyridines with MEMCl:
To a solution of 3Hꢀimidazo[4,5ꢀb]pyridine (1 equiv) in dry toluene was added
triethylamine (1.5 equiv). The reaction was stirred at 0 °C for 30 minutes. A solution of 2ꢀ
methoxyethoxymethyl chloride (MEMCl) (2 equiv) in toluene was added to the mixture
via a dropping funnel over a period of one hour at 0 °C. The reaction mixture was then
heated to reflux (110 °C) overnight. The solvent was evaporated under reduced pressure
and the residue purified by column chromatography (Cyclohexane/AcOEt) to give the
N3ꢀprotectedꢀ3Hꢀimidazo[4,5ꢀb]pyridine.
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Preparation of 6-bromo-3-((2-methoxyethoxy)methyl)-3H-imidazo[4,5-b]pyridine
(3a): The reaction was carried out following procedure B and starting from 6ꢀbromoꢀ3Hꢀ
imidazo[4,5ꢀb]pyridine a (3.00 g, 15.15 mmol), MEMCl (3.77 g, 30.30 mmol) and
triethylamine (3.16 mL) in 250 mL toluene to give 3a (1.68 g, 40 %) as an orange oil; 1H
NMR (300 MHz, CDCl3) δ (ppm) 8.46 (d, J = 1.0 Hz, 1H), 8.22 (t, J = 3.0 Hz, 2H), 5.73
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(s, 2H), 3.74 – 3.64 (m, 2H), 3.55 – 3.47 (m, 2H), 3.34 (s, 3H); MS (ES+) m/z (%): 286.0
(100) [M+H]+. Spectroscopic data were in agreement with those reported in the
literature.28
9
Preparation of 5-chloro-3-((2-methoxyethoxy)methyl)-3H-imidazo[4,5-b]pyridine
(3b): 5ꢀchloroꢀ3Hꢀimidazo[4,5ꢀb]pyridine b was prepared following procedure A from
commercially available 2,3ꢀdiaminoꢀ6ꢀchloropyridine (8.55 g, 59.55 mmol) in
trimethylorthoformate (195 mL) to give b (9.00 g, 98 %) as a grey solid; mp: 224 – 226
°C; 1H NMR (300 MHz, DMSOꢀd6) δ (ppm) 8.50 (s, 1H), 8.07 (d, J = 8.3 Hz, 1H), 7.29
(d, J = 8.3 Hz, 1H); 13C NMR (75 MHz, DMSOꢀd6) δ (ppm) 151.6, 145.2, 143.7, 128.4,
126.1, 117.6; MS (ES+) m/z (%): 154.0 (100) [M+H]+; HRMS (ESI) calculated for
C6H5N3Cl 154.0172 found 154.0172.
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Compound 3b was prepared following procedure B starting from 5ꢀchloroꢀ3Hꢀ
imidazo[4,5ꢀb]pyridine b (3.00 g, 19.54 mmol), MEMCl (4.87 g, 39.07 mmol) and
1
triethylamine (4.07 mL) in 300 mL toluene to give 3b (2.70 g, 57 %) as a yellow oil; H
NMR (300 MHz, CDCl3) δ (ppm) 8.22 (s, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 8.3
Hz, 1H), 5.73 (s, 2H), 3.75 – 3.70 (m, 2H), 3.55 – 3.49 (m, 2H), 3.35 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ (ppm) 146.1, 145.9, 144.4, 133.7, 130.1, 118.9, 72.7, 71.2, 68.7, 58.7;
MS (ES+) m/z (%): 242.1 (100) [M+H]+; HRMS (ESI) calculated for C10H13N3O2Cl
242.0696 found 242.0691.
Preparation of 6-bromo-7-chloro-3-((2-methoxyethoxy)methyl)-3H-imidazo[4,5-
b]pyridine (3c): 6ꢀbromoꢀ7ꢀchloroꢀ3Hꢀimidazo[4,5ꢀb]pyridine c was prepared starting
from 6ꢀbromoꢀ3Hꢀimidazo[4,5ꢀb]pyridine a. Compound a (3.00 g, 15.15 mmol) in AcOH
(18 mL) was added m-chloroperbenzoic acid (7.47 g, 30.30 mmol, 2 equiv). The reaction
mixture was stirred at room temperature for 3 days then filtered on a sintered glass disk to
allow a first fraction of 6ꢀbromoꢀ3Hꢀimidazo[4,5ꢀb]pyridine 4ꢀoxide. The filtrate was
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concentrated under reduced pressure, taken in AcOEt and filtered again to allow a second
fraction of the Nꢀoxide. Both fractions of 6ꢀbromoꢀ3Hꢀimidazo[4,5ꢀb]pyridine 4ꢀoxide
were taken in AcOEt and the resulting suspension was refluxed for 1 h. Subsequent
filtration on sintered glass disk furnished 6ꢀbromoꢀ3Hꢀimidazo[4,5ꢀb]pyridine 4ꢀoxide
with no trace of benzoic acid. The solid was distributed into microwave tubes in 250 mg
portions and POCl3 (1.5 mL) was added in each tube. The reaction mixture was heated
under microwave irradiation at 80 °C for 10 min. Subsequently, the crude materials were
poured on ice and neutralized with a 3 M NaOH aqueous solution and the aqueous layer
was extracted with AcOEt. The combined organic layers were dried with anhydrous
MgSO4 and concentrated under reduced pressure. The resulting product c (1.43 g, 40 %) a
beige solid, is an inseparable mixture of 2 regiosiomers: 7ꢀchloro and 5ꢀchloroꢀ
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1
imidazo[4,5ꢀb]pyridine in 85/15 ratio respectively; mp: 199 – 201 °C; H NMR (300
MHz, DMSOꢀd6) δ 13.54 (bs, 1H), 8.57 (s, 2H), 8.50 (s, 0.3H); 13C NMR (75 MHz,
DMSOꢀd6) δ (ppm) 146.6, 145.8, 145.5, 142.3, 133.7, 133.2, 132.3, 130.4, 128.8, 127.8,
113.1, 111.1; MS (ES+) m/z (%): 231.9 (100) [M+H]+, 273.0 (20) [M+CH3CN+H]+;
HRMS (ESI) calculated for C6H4N3ClBr 231.9277 found 231.9287.
Compound 3c was prepared following procedure B starting from 6ꢀbromoꢀ7ꢀchloroꢀ3Hꢀ
imidazo[4,5ꢀb]pyridine c (1.85 g, 7.94 mmol), MEMCl (1.98 g, 15.88 mmol) and
triethylamine (1.66 mL) in 150 mL toluene to give 3c (1.62 g, 64 %) as a yellow solid;
1
mp: 72 – 74 °C; H NMR (300 MHz, CDCl3) δ (ppm) 8.36 (s, 1H), 8.15 (s, 1H), 5.61 (s,
2H), 3.66 – 3.52 (m, 2H), 3.44 – 3.35 (m, 2H), 3.20 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ (ppm) 147.0, 146.4, 145.5, 135.3, 134.5, 115.5, 73.5, 71.7, 69.3, 59.2; MS (ES+) m/z
(%): 322.0 (100) [M+H]+; HRMS (ESI) calculated for C10H12N3O2ClBr 319.9801 found
319.9803.
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Preparation of 3-((2-methoxyethoxy)methyl)-3H-imidazo[4,5-b]pyridine (3h): 3Hꢀ
imidazo[4,5ꢀb]pyridine d was prepared following procedure A with commercially
available pyridineꢀ2,3ꢀdiamine (2.00 g, 18.33 mmol) in trimethylorthoformate (60 mL) to
give d (1.63 g, 74 %) as a dark red solid; mp: 150 – 152 °C; 1H NMR (300 MHz, DMSOꢀ
d6) δ (ppm) 8.43 (s, 1H), 8.34 (d, J = 4.5 Hz, 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.22 (dd, J =
4.5, 7.9 Hz, 1H). Spectroscopic data were in agreement with those reported in the
literature.27
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Compound 3h was prepared following procedure B starting from 3Hꢀimidazo[4,5ꢀ
b]pyridine d (0.60 g, 5.04 mmol), MEMCl (1.25 g, 10.07 mmol) and triethylamine (1.05
1
mL) in 80 mL toluene to give 3h (0.63 g, 60 %) as an yellow oil; H NMR (300 MHz,
CDCl3) δ (ppm) 8.07 (dd, J = 4.8, 0.9 Hz, 1H), 7.98 (s, 1H), 7.74 (dd, J = 8.0, 0.9 Hz,
1H), 6.91 (dd, J = 8.0, 4.8 Hz, 1H), 5.43 (s, 2H), 3.41 – 3.38 (m, 2H), 3.17 – 3.14 (m,
2H), 2.98 (s, 3H). Spectroscopic data were in agreement with those reported in the
literature.28
Typical procedure
C
for the Suzuki coupling of 6-bromo-3-((2-
methoxyethoxy)methyl)-3H-imidazo[4,5-b]pyridine: In a roundꢀbottom flask and under
argon inlet, to a solution of 6ꢀbromoꢀ3ꢀ((2ꢀmethoxyethoxy)methyl)ꢀ3Hꢀimidazo[4,5ꢀ
b]pyridine (3.50 mmol, 1 equiv) in 1,4ꢀdioxane (6 mL), were added PdCl2(dppf) (0.35
mmol, 0.1 equiv) and an aqueous solution of Cs2CO3 (2M) (13.98 mmol, 4 equiv). Then,
the boronic acid (10.48 mmol, 3 equiv) was slowly added. The reaction mixture was
stirred at 100 °C for 12 hours. The mixture was extracted with AcOEt (3x) and the
organic layers dried with MgSO4. Purification by flash column chromatography
(Cyclohexane/AcOEt 80/20) afforded the desired products.
3-((2-methoxyethoxy)methyl)-6-phenyl-3H-imidazo[4,5-b]pyridine (3d): procedure C
1
afforded 3d (0.65 g, 66 %) as a green solid; H NMR (300 MHz, CDCl3) δ (ppm) 8.64
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(d, J = 1.4 Hz, 1H), 8.38 – 8.12 (m, 2H), 7.60 (m, 2H), 7.47 (m, 2H), 7.39 (m, 1H), 5.77
(s, 2H), 3.78 – 3.67 (m, 2H), 3.55 – 3.47 (m, 2H), 3.34 (s, 3H); MS (ES+) m/z (%): 284.1
(100) [M+H]+; HRMS (ESI) calculated for C16H18N3O2 284.1399 found 284.1400.
Spectroscopic data were in agreement with those reported in the literature.28
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procedure C afforded 3e (1.07 g, 98 %) as a green solid; mp: 68 – 70 °C; H NMR (300
MHz, CDCl3) δ (ppm) 8.58 (d, J = 1.9 Hz, 1H), 8.23 (s, 1H), 8.18 (d, J = 1.9 Hz, 1H),
7.51 (d, J = 8.7 Hz, 2H), 6.99 (d, J = 8.7 Hz, 2H), 5.74 (s, 2H), 3.83 (s, 3H), 3.75 – 3.68
(m, 2H), 3.53 – 3.46 (m, 2H), 3.32 (s, 3H); 13C (75 MHz, CDCl3) δ (ppm) 159.4, 146.2,
144.8, 144.0, 135.2, 132.7, 131.0, 128.6, 126.0, 114.6, 73.0, 71.6, 68.9, 59.1, 55.4; MS
(ES+) m/z (%): 314.2 (100) [M+H]+; HRMS (ESI) calculated for C17H20N3O3 314.1505
found 314.1509.
2-fluoro-4-(3-((2-methoxyethoxy)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)benzonitrile
1
(3f): procedure C afforded 3f (0.91 g, 80 %) as a brown solid; mp: 173 – 175 °C; H
NMR (300 MHz, CDCl3) δ (ppm) 8.65 (s, 1H), 8.41 (s, 1H), 8.28 (s, 1H), 7.75 (t, J = 7.2
Hz, 1H), 7.50 (dd, J = 13.4, 9.3 Hz, 2H), 5.81 (s, 2H), 3.79 – 3.70 (m, 2H), 3.57 – 3.50
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(m, 2H), 3.34 (s, 3H); 13C NMR (75 MHz, CDCl3) δ (ppm) 163.6 (d, JC-F = 259.6 Hz),
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146.0, 145.9, 144.1, 134.2, 130.2, 126.6, 123.9 (d, JC-F =3.3 Hz), 115.5, 115.2, 113.9,
100.6, 100.4, 73.4, 71.7, 69.3, 59.2; MS (ES+) m/z (%): 327.1 (100) [M+H]+; HRMS
(ESI) calculated for C17H16N4O2F 327.1257 found 327.1255.
3-((2-methoxyethoxy)methyl)-6-(pyridine-4-yl)-3H-imidazo[4,5-b]pyridine (3g): In a
sealed tube and under argon inlet, Pd(PPh3)4 (300 mg, 0.26mmol, 0.1 equiv) was added to
a solution of 6ꢀbromoꢀ3ꢀ((2ꢀmethoxyethoxy)methyl)ꢀ3Hꢀimidazo[4,5ꢀb]pyridine (744 mg,
2.60 mmol) in a mixture of 1,4ꢀdioxane/H2O 4/1 (15 mL) followed by K2CO3 (1.08 g,
7.80 mmol, 3equiv) and the boronic acid (639 mg, 5.20 mmol, 2 equiv). The reaction
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mixture was stirred at 110 °C for 12 hours. After cooling to room temperature, the
mixture was extracted with AcOEt (3x) and the organic layers dried with MgSO4.
Purification by flash column chromatography (Dichloromethane/EtOH 95/5) afforded 3g
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1
as a beige solid (600 mg, 80 %); mp: 53 – 55 °C; H NMR (300 MHz, CDCl3) δ (ppm)
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8.73 – 8.72 (m, 3H), 8.32 (d, J = 2.0 Hz, 1H), 8.30 (s, 1H), 7.56 (d, J = 6.1 Hz, 2H), 5.80
(s, 2H), 3.79 – 3.68 (m, 2H), 3.59 – 3.45 (m, 2H), 3.35 (s, 3H); 13C (75 MHz, CDCl3) δ
(ppm) 150.2, 147.5, 145.8, 145.5, 143.6, 135.2, 129.6, 126.3, 121.7, 72.9, 71.4, 68.8,
58.9; MS (ES+) m/z (%): 285.1 (100) [M+H]+; HRMS (ESI) calculated for
C15H17N4O2 285.1352 found 285.1353.
Typical procedure for the synthesis of 1,1-dibromoalkenes (4): 1,1ꢀdibromoalkenes
were synthesized according to the Ramirez procedure starting from commercially
available aldehydes.29 The typical procedure for their preparation is as follows, presenting
2ꢀbromoꢀ4ꢀ(2,2ꢀdibromovinyl)ꢀ1ꢀmethoxybenzene as an example:30
2-bromo-4-(2,2-dibromovinyl)-1-methoxybenzene (4k): In a roundꢀbottom flask and
under argon inlet, a solution of PPh3 (10.98 g, 41.85 mmol, 3 equiv) in dichloromethane
(30 mL) was slowly added via a dropping funnel to a solution of 3ꢀbromoꢀ4ꢀ
methoxybenzaldehyde (3.00 g, 13.95 mmol), carbon tetrabromide (6.94 g, 20.93 mmol,
1.5 equiv) in dichloromethane (100 mL) at 0 °C. The reaction mixture was stirred
overnight at room temperature. The solvent was evaporated under reduced pressure.
Purification by flash column chromatography (Cyclohexane) afforded dibromoalkene 4k,
a yellow solid (1.80 g, 35 %); mp: 58 – 60 °C; 1H NMR (300 MHz, CDCl3) δ (ppm) 7.76
(d, J = 2.1 Hz, 1H), 7.47 (dd, J = 8.6, 2.1 Hz, 1H), 7.34 (s, 1H), 6.87 (d, J = 8.6 Hz, 1H),
3.90 (s, 3H); 13C (75 MHz, CDCl3) δ (ppm) 155.7, 134.8, 133.0, 128.8, 128.8, 111.4,
111.3, 88.8, 56.2; HRMS (APPI) calculated for C9H7Br3O 367.8046 found 367.8038.
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Compounds 4a,31 4b,31 4c,32 4d,31 4e,334f,33 4g,34 4h, 354i,33 4j,32 4l,36 4m37 and 4n32
showed satisfactory spectroscopic data in agreement with those reported in the literature.
Typical procedure D for the direct alkynylation between 3H-imidazo[4,5-b]pyridines
and 1,1-dibromoalkenes: In a roundꢀbottom flask, N3ꢀprotectedꢀ3Hꢀimidazo[4,5ꢀ
b]pyridine (1 equiv), copper catalyst (0.1 equiv), DPEPhos (0.2 equiv) and 1,4ꢀdioxane
(2 mL) were mixed under argon inlet for 5 minutes at room temperature. LiOtBu (6
equiv) was then added, the reaction mixture was stirred for 1 min and 1,1ꢀdibromoalkene
(2 equiv) was added. The mixture was stirred at 110 °C for 4 hours. The crude reaction
mixture was allowed to cool to room temperature. AcOEt was added to the mixture,
which was filtered through celite. The solvents were evaporated under reduced pressure.
Purification by flash column chromatography (Cyclohexane/AcOEt 95/5) afforded the
desired alkynes. It should be noticed that the direct alkynylation reaction was performed
in a sealed tube for compounds 5a, 5b, 6a, 6b, 7a, 7d, 7e, 7f, 7m, 8g and 8j which gave
better results than if performed in a flask.
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3-benzyl-6-bromo-2-(phenylethynyl)-3H-imidazo[4,5-b]pyridine (5a): The reaction
carried out following procedure D starting from 3Hꢀimidazo[4,5ꢀb]pyridine 1 (100 mg,
0.35 mmol) and CuBr.SMe2 (7.13 mg, 0.04 mmol) as the copper catalyst in a sealed tube
afforded 5a (90 mg, 66 %) as a brown solid after flash chromatography followed by
recrystallization in cyclohexane; mp: 127 – 129 °C; 1H NMR (300 MHz, CDCl3) δ (ppm)
8.48 (s, 1H), 8.17 (s, 1H), 7.59 (d, J = 6.9 Hz, 2H), 7.50 – 7.37 (m, 5H), 7.30 (d, J = 6.7
Hz, 3H), 5.60 (s, 2H); 13C NMR (75 MHz, CDCl3) δ (ppm) 146.3, 145.6, 139.5, 136.4,
135.9, 132.3, 130.4, 129.9, 129.0, 128.8, 128.3, 128.1, 120.6, 114.8, 97.2, 78.7, 47.2; MS
(ES+) m/z (%): 390.0 (100) [M+H]+; HRMS (ESI) calculated for C21H15N3Br 388.0449
found 388.0454.
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3-benzyl-6-bromo-2-(naphthalen-2-ylethynyl)-3H-imidazo[4,5-b]pyridine (5b): The
reaction carried out following procedure D starting from 3Hꢀimidazo[4,5ꢀb]pyridine 1
(100 mg, 0.35 mmol) and CuBr.SMe2 (7.13 mg, 0.04 mmol) as the copper catalyst in a
sealed tube afforded 5b (64 mg, 42 %) as a yellow solid after flash chromatography
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followed by recrystallization in cyclohexane; mp: 202 – 204 °C; H NMR (300 MHz,
CDCl3) δ (ppm) 8.49 (s, 1H), 8.18 (s, 1H), 8.12 (s, 1H), 7.85 (d, J = 7.5 Hz, 3H), 7.57 (t,
J = 8.5 Hz, 3H), 7.46 (d, J = 6.7 Hz, 2H), 7.33 (d, J = 7.2 Hz, 3H), 5.64 (s, 2H); 13C NMR
(75 MHz, CDCl3) δ (ppm) 146.3, 145.6, 136.5, 136.0, 133.7, 133.2, 132.8, 129.9, 129.0,
128.6, 128.4, 128.2, 128.1, 128.0, 127.9, 127.9, 127.2, 117.8, 114.9, 97.7, 79.0, 47.2; MS
(ES+) m/z (%): 440.1 (100) [M+H]+; HRMS (ESI) calculated for C25H17N3Br 438.0606
found 438.0608.
6-bromo-3-(4-methoxybenzyl)-2-(phenylethynyl)-3H-imidazo[4,5-b]pyridine
(6a):
The reaction carried out following procedure D starting from 3Hꢀimidazo[4,5ꢀb]pyridine
2 (100 mg, 0.31 mmol) and CuBr.SMe2 (6.46 mg, 0.03 mmol) as the copper catalyst in a
sealed tube afforded 6a (84 mg, 65 %) as a brown solid after flash chromatography
followed by recrystallization in a mixture of cyclohexane/dichloromethane; mp: 176 –
1
178 °C; H NMR (300 MHz, CDCl3) δ (ppm) 8.48 (s, 1H), 8.16 (s, 1H), 7.64 – 7.62 (m,
2H), 7.55 – 7.29 (m, 5H), 6.85 – 6.82 (m, 2H), 5.54 (s, 2H), 3.76 (s, 3H); 13C NMR (75
MHz, CDCl3) δ (ppm) 159.6, 146.2, 136.4, 134.3, 132.3, 130.4, 130.2, 129.8, 129.7,
128.8, 128.1, 120.7, 114.8, 114.2, 97.1, 78.9, 55.4, 46.7; MS (ES+) m/z (%): 420.1 (100)
[M+H]+; HRMS (ESI) calculated for C22H17N3OBr 418.0555 found 418.0563.
6-bromo-3-(4-methoxybenzyl)-2-(naphthalen-2-ylethynyl)-3H-imidazo[4,5-b]-
pyridine (6b): The reaction carried out following procedure D starting from 3Hꢀ
imidazo[4,5ꢀb]pyridine 2 (100 mg, 0.31 mmol) and CuBr.SMe2 (6.46 mg, 0.03 mmol) as
the copper catalyst in a sealed tube afforded 6b (87 mg, 60 %) as a white solid after flash
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chromatography
followed
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cyclohexane/dichloromethane; mp: 154 – 156 °C; H NMR (300 MHz, CDCl3) δ (ppm)
8.48 (d, J = 1.9 Hz, 1H), 8.15 (s, 1H), 8.14 (s, 1H), 7.85 (dd, J = 8.7, 2.8 Hz, 3H), 7.62
(dd, J = 7.5, 0.9 Hz, 1H), 7.55 (t, J = 4.5 Hz, 2H), 7.44 (d, J = 8.6 Hz, 2H), 6.85 (d, J =
8.6 Hz, 2H), 5.56 (s, 2H), 3.75 (s, 3H); 13C NMR (75 MHz, CDCl3) δ (ppm) 159.6, 146.2,
145.5, 139.4, 136.5, 133.7, 133.1, 132.8, 129.8, 129.7, 128.6, 128.2, 128.0, 127.9, 127.2,
117.8, 114.8, 114.3, 97.6, 79.1, 55.4, 46.7; MS (ES+) m/z (%): 470.1 (35) [M+H]+;
HRMS (ESI) calculated for C26H19N3OBr 468.0711 found 468.0726.
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6-bromo-3-((2-methoxyethoxy)methyl)-2-(phenylethynyl)-3H-imidazo[4,5-b]pyridine
(7a): The reaction carried out following procedure D starting from 3Hꢀimidazo[4,5ꢀ
b]pyridine 3a (100 mg, 0.35 mmol) and Cu(OAc)2 (6.35 mg, 0.04 mmol) as the copper
catalyst in a sealed tube afforded 7a (62 mg, 46 % versus 19 % with CuBr.SMe2) as an
orange solid after flash chromatography followed by recrystallization in a mixture of
cyclohexane/dichloromethane; mp: 70 – 72 °C; 1H NMR (300 MHz, CDCl3) δ (ppm)8.48
(d, J = 2.0 Hz, 1H), 8.17 (d, J = 2.0 Hz, 1H), 7.70 – 7.61 (m, 2H), 7.50 – 7.36 (m, 3H),
5.87 (s, 2H), 3.82 – 3.75 (m, 2H), 3.55 – 3.49 (m, 2H), 3.33 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ (ppm) 146.5, 145.8, 139.9, 136.3, 132.5, 130.5, 130.0, 128.8, 120.5, 115.2,
97.2, 78.1, 72.9, 71.6, 69.5, 59.2; MS (ES+) m/z (%): 386.1 (100) [M+H]+; HRMS (ESI)
calculated for C18H17N3O2Br 386.0504 found 386.0511.
6-bromo-3-((2-methoxyethoxy)methyl)-2-(naphtalen-2-ylethynyl)-3H-imidazo[4,5-b]-
pyridine (7b): The reaction carried out following procedure D starting from 3Hꢀ
imidazo[4,5ꢀb]pyridine 3a (100 mg, 0.35 mmol) and Cu(OAc)2 (6.35 mg, 0.04 mmol) as
the copper catalyst afforded 7b (118mg, 77 % versus 33 % with CuBr.SMe2) as a white
solid after flash chromatography followed by recrystallization in a mixture of
1
cyclohexane/dichloromethane; mp: 117 – 119 °C; H NMR (300 MHz, CDCl3) δ (ppm)
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8.48 (d, J = 2.0 Hz, 1H), 8.21 – 8.17 (m, 2H), 7.87 – 7.84 (m, 3H), 7.65 (dd, J = 8.5, 1.5
Hz, 1H), 7.57 – 7.54 (m, 2H), 5.91 (s, 2H), 3.88 – 3.76 (m, 2H), 3.59 – 3.47 (m, 2H), 3.35
(s, 3H); 13C NMR (75 MHz, CDCl3) δ (ppm) 146.5, 145.8, 140.0, 136.4, 133.8, 133.4,
132.8, 130.0, 128.6, 128.2, 128.0, 128.0, 127.9, 127.2, 117.7, 115.2, 97.8, 78.4, 72.9,
71.6, 69.5, 59.2; MS (ES+) m/z (%): 438.1 (100) [M+H]+; HRMS (ESI) calculated for
C22H19N3O2Br 436.0661 found 436.0662.
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2-([1,1’-biphenyl]-4-ylethynyl)-6-bromo-3-((2-methoxyethoxy)methyl)-3H-imidazo-
[4,5-b]pyridine (7c): The reaction carried out following procedure D starting from 3Hꢀ
imidazo[4,5ꢀb]pyridine 3a (100 mg, 0.35 mmol) and CuBr.SMe2 (6.46 mg, 0.04 mmol) as
the copper catalyst afforded 7c (71 mg, 44 %) as a yellowish solid after flash
chromatography
followed
by
recrystallization
in
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of
1
cyclohexane/dichloromethane; mp: 139 – 141 °C; H NMR (300 MHz, CDCl3) δ (ppm)
8.48 (s, 1H), 8.17 (s, 1H), 7.78 – 7.56 (m, 6H), 7.53 – 7.37 (m, 3H), 5.88 (s, 2H), 3.82 –
3.79 (m, 2H), 3.54 – 3.52 (m, 2H), 3.35 (s, 3H); 13C NMR (75 MHz, CDCl3) δ (ppm)
146.4, 145.7, 143.1, 139.8, 139.8, 136.3, 132.8, 129.9, 129.0, 128.1, 127.3, 127.1, 119.2,
115.1, 97.2, 78.7, 72.8, 71.5, 69.4, 59.1; MS (ES+) m/z (%): 464.1 (100) [M+H]+; HRMS
(ESI) calculated for C24H21N3O2Br 462.0817 found 462.0818.
6-bromo-3-((2-methoxyethoxy)methyl)-2-(p-tolylethynyl)-3H-imidazo[4,5-b]pyridine
(7d): The reaction carried out following procedure D starting from 3Hꢀimidazo[4,5ꢀ
b]pyridine 3a (100 mg, 0.35 mmol) and CuBr.SMe2 (6.46 mg, 0.04 mmol) as the copper
catalyst in a sealed tube afforded 7d (74 mg, 53 % versus 48 % with Cu(OAc)2) as a light
yellow solid after flash chromatography followed by recrystallization in a mixture of
cyclohexane/dichloromethane; mp: 89 – 91 °C; 1H NMR (300 MHz, CDCl3) δ (ppm) 8.44
(d, J = 1.9 Hz, 1H), 8.13 (d, J = 1.9 Hz, 1H), 7.51 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.0 Hz,
2H), 5.84 (s, 2H), 3.78 – 3.75 (m, 2H), 3.58 – 3.42 (m, 2H), 3.32 (s, 3H), 2.38 (s, 3H); 13C
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NMR (75 MHz, CDCl3) δ (ppm) 146.2, 145.7, 141.0, 140.1, 136.3, 132.3, 129.8, 129.5,
117.4, 115.1, 97.7, 77.6, 72.8, 71.5, 69.4, 59.2, 21.8; MS (ES+) m/z (%): 402.1 (100)
[M+H]+; HRMS (ESI) calculated for C19H19N3O2Br 400.0661 found 400.0657.
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6-bromo-3-((2-methoxyethoxy)methyl)-2-(o-tolylethynyl)-3H-imidazo[4,5-b]pyridine
(7e): The reaction carried out following procedure D starting from 3Hꢀimidazo[4,5ꢀ
b]pyridine 3a (100 mg, 0.35 mmol) and CuBr.SMe2 (6.46 mg, 0.04 mmol) as the copper
catalyst in a sealed tube afforded 7e (84 mg, 60 %) as a brown solid after flash
chromatography; mp: 64 – 66 °C; 1H NMR (300 MHz, CDCl3) δ (ppm) 8.45 (s, 1H), 8.14
(s, 1H), 7.59 (d, J = 7.5 Hz, 1H), 7.38 – 7.12 (m, 3H), 5.84 (s, 2H), 3.81 – 3.69 (m, 2H),
3.53 – 3.43 (m, 2H), 3.30 (s, 3H), 2.56 (s, 3H); 13C NMR (75 MHz, CDCl3) δ (ppm)
146.4, 141.6, 136.4, 133.0, 130.5, 130.2, 130.0, 130.0, 128.8, 126.0, 120.4, 115.2, 96.4,
81.8, 72.8, 71.5, 69.4, 59.2, 21.0; MS (ES+) m/z (%): 400.1 (100) [M+H]+; HRMS (ESI)
calculated for C19H19N3O2Br 400.0661 found 400.0652.
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[4,5-b]pyridine (7f): The reaction carried out following procedure D starting from 3Hꢀ
imidazo[4,5ꢀb]pyridine 3a (100 mg, 0.35 mmol) and CuBr.SMe2 (6.46 mg, 0.04 mmol) as
the copper catalyst in a sealed tube afforded 7f (76 mg, 52 % versus 53 % with Cu(OAc)2)
as a yellow solid after flash chromatography followed by recrystallization in a mixture of
1
cyclohexane/dichloromethane; mp: 137 – 139 °C; H NMR (300 MHz, CDCl3) δ (ppm)
8.44 (d, J = 1.8 Hz, 1H), 8.13 (d, J = 1.8 Hz, 1H), 7.57 (d, J = 8.8 Hz, 2H), 6.90 (d, J =
8.8 Hz, 2H), 5.84 (s, 2H), 3.83 (s, 3H), 3.80 – 3.75 (m, 2H), 3.53 – 3.48 (m, 2H), 3.32 (s,
3H); 13C NMR (75 MHz, CDCl3) δ (ppm) 161.3, 146.1, 145.8, 136.4, 134.1, 130.1, 129.8,
115.0, 114.5, 112.4, 97.8, 77.3, 72.8, 71.5, 69.4, 59.2, 55.5; MS (ES+) m/z (%): 416.1
(100) [M+H]+; HRMS (ESI) calculated for C19H19N3O3Br 416.0610 found 416.0609.
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2-((3,4-bis((tert-butyldimethylsilyl)-oxy)phenyl)ethynyl)-6-bromo-3-((2-methoxy-
ethoxy)methyl)-3H-imidazo[4,5-b]pyridine (7g): The reaction carried out following
procedure D starting from 3Hꢀimidazo[4,5ꢀb]pyridine 3a (100 mg, 0.35 mmol) and
CuBr.SMe2 (6.46 mg, 0.04 mmol) as the copper catalyst afforded 7g (124 mg, 55 %) as a
beige solid after flash chromatography followed by recrystallization in a mixture of
cyclohexane/dichloromethane; mp: 95 – 97 °C; 1H NMR (300 MHz, CDCl3) δ (ppm) 8.46
(d, J = 1.4 Hz, 1H), 8.15 (d, J = 1.3 Hz, 1H), 7.15 (dd, J = 8.2, 2.0 Hz, 1H), 7.11 (d, J =
1.9 Hz, 1H), 6.84 (d, J = 8.2 Hz, 1H), 5.85 (s, 2H), 3.82 – 3.75 (m, 2H), 3.54 – 3.48 (m,
2H), 3.33 (s, 3H), 1.00 (s, 9H), 0.99 (s, 9H), 0.23 (s, 6H), 0.22 (s, 6H); 13C NMR (75
MHz, CDCl3) δ (ppm) 149.9, 147.1, 146.1, 145.7, 140.3, 136.3, 129.7, 126.5, 124.7,
121.3, 115.0, 112.9, 97.8, 72.7, 71.5, 69.4, 59.1, 25.9, 18.5, 18.4, ꢀ 4.0, ꢀ 4.3; MS (ES+)
m/z (%): 648.2 (100) [M+H]+; HRMS (ESI) calculated for C30H45N3O4BrSi2 646.2132
found 646.2120.
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b]pyridine (7h): The reaction carried out following procedure D starting from 3Hꢀ
imidazo[4,5ꢀb]pyridine 3a (100 mg, 0.35 mmol) and CuBr.SMe2 (6.46 mg, 0.04 mmol) as
the copper catalyst afforded 7h (51 mg, 36 % versus 32 % with Cu(OAc)2) as a brown
1
solid after flash chromatography; mp: 71 – 73 °C; H NMR (300 MHz, CDCl3) δ (ppm)
8.47 (d, J = 1.8 Hz, 1H), 8.16 (d, J = 1.8 Hz, 1H), 7.47 – 7.29 (m, 3H), 7.14 (d, J = 7.2
Hz, 1H), 5.85 (s, 2H), 3.78 – 3.75 (m, 2H), 3.52 – 3.49 (m, 2H), 3.32 (s, 3H); 13C NMR
1
(75 MHz, CDCl3) δ (ppm) 162.4 (d, JC-F = 248.1 Hz), 146.7, 145.7, 139.4, 136.2, 130.5
3
4
3
(d, JC-F = 8.5 Hz), 130.2, 128.4 (d, JC-F = 3.2 Hz), 122.3 (d, JC-F = 9.4 Hz), 119.2 (d,
2
4
2JC-F = 23.5 Hz), 117.9 (d, JC-F = 21.2 Hz), 115.3, 95.5 (d, JC-F = 3.4 Hz), 78.7, 72.8,
71.6, 69.5, 59.2; MS (ES+) m/z (%): 406.0 (100) [M+H]+; HRMS (ESI) calculated for
C18H16N3O2FBr 404.0410 found 404.0405.
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6-bromo-2-((4-chlorophenyl)ethynyl)-3-((2-methoxyethoxy)methyl)-3H-imidazo[4,5-
b]pyridine (7i): The reaction carried out following procedure D starting from 3Hꢀ
imidazo[4,5ꢀb]pyridine 3a (100 mg, 0.35 mmol) and CuBr.SMe2 (6.46 mg, 0.04 mmol) as
the copper catalyst afforded 7i (80 mg, 54 % versus 37 % with Cu(OAc)2) as a yellowish
solid after flash chromatography followed by recrystallization in a mixture of
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cyclohexane/dichloromethane; mp: 118 – 120 °C; H NMR (300 MHz, CDCl3) δ (ppm)
8.46 (d, J = 1.5 Hz, 1H), 8.14 (d, J = 1.6 Hz, 1H), 7.56 (d, J = 8.3 Hz, 2H), 7.37 (d, J =
8.3 Hz, 2H), 5.83 (s, 2H), 3.85 – 3.71 (m, 2H), 3.59 – 3.44 (m, 2H), 3.32 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ (ppm) 146.5, 145.7, 136.7, 136.2, 133.5, 130.0, 129.2, 118.9,
115.2, 95.8, 78.9, 72.7, 71.5, 69.4, 59.1; MS (ES+) m/z (%): 422.0 (100) [M+H]+; HRMS
calculated for C18H16N3O2ClBr 420.0114 found 420.0114.
6-bromo-2-((3-bromophenyl)ethynyl)-3-((2-methoxyethoxy)methyl)-3H-imidazo[4,5-
b]pyridine (7j): The reaction carried out following procedure D starting from 3Hꢀ
imidazo[4,5ꢀb]pyridine 3a (100 mg, 0.35 mmol) and CuBr.SMe2 (6.46 mg, 0.04 mmol) as
the copper catalyst afforded 7j (83 mg, 51 %) as a white solid after flash chromatography
followed by recrystallization in a mixture of cyclohexane/dichloromethane; mp: 91 – 93
°C; 1H NMR (300 MHz, CDCl3) δ (ppm) 8.49 (s, 1H), 8.18 (s, 1H), 7.79 (s, 1H), 7.58 (d,
J = 7.5 Hz, 2H), 7.37 – 7.17 (m, 1H), 5.87 (s, 2H), 3.87 – 3.70 (m, 2H), 3.61 – 3.45 (m,
2H), 3.35 (s, 3H); 13C NMR (75 MHz, CDCl3) δ (ppm) 146.7, 145.7, 136.2, 134.9, 133.5,
130.9, 130.2, 130.1, 122.5, 122.4, 115.2, 95.2, 79.1, 72.8, 71.6, 69.4, 59.2; MS (ES+) m/z
(%): 466.0 (100) [M+H]+; HRMS (ESI) calculated for C18H16N3O2Br2 463.9609 found
463.9602.
6-bromo-2-((3-bromo-4-methoxyphenyl)-ethynyl)-3-((2-methoxyethoxy)methyl)-3H-
imidazo[4,5-b]pyridine (7k): The reaction carried out following procedure D starting
from 3Hꢀimidazo[4,5ꢀb]pyridine 3a (100 mg, 0.35 mmol) and CuBr.SMe2 (6.46 mg, 0.04
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mmol) as the copper catalyst afforded 7k (81 mg, 47 % versus 21 % with Cu(OAc)2) as a
yellow solid after flash chromatography followed by recrystallization in a mixture of
cyclohexane/dichloromethane; mp: 136 – 138 °C;1H NMR (300 MHz, CDCl3) δ (ppm)
8.45 (d, J = 2.0 Hz, 1H), 8.14 (d, J = 2.0 Hz, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.57 (dd, J =
8.6, 2.0 Hz, 1H), 6.90 (d, J = 8.6 Hz, 1H), 5.83 (s, 2H), 3.93 (s, 3H), 3.78 – 3.75 (m, 2H),
3.53 – 3.50 (m, 2H), 3.34 (s, 3H); 13C NMR (75 MHz, CDCl3) δ (ppm) 157.7, 146.4,
145.8, 139.8, 137.0, 136.3, 133.2, 130.0, 115.2, 113.8, 111.9, 111.8, 95.9, 78.1, 72.8,
71.6, 69.4, 59.2, 56.5; MS (ES+) m/z (%): 496.0 (100) [M+H]+; HRMS (ESI) calculated
for C19H18N3O3Br2 493.9715 found 493.9719.
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6-bromo-3-((2-methoxyethoxy)methyl)-2-((4-(trifluoromethyl)phenyl)ethynyl)-3H-
imidazo[4,5-b]pyridine (7l): The reaction carried out following procedure D starting
from 3Hꢀimidazo[4,5ꢀb]pyridine 3a (100 mg, 0.35 mmol) and CuBr.SMe2 (6.46 mg, 0.04
mmol) as the copper catalyst afforded 7l (48 mg, 31 % versus 28 % with Cu(OAc)2) as a
white solid after flash chromatography followed by recrystallization in a mixture of
1
cyclohexane/dichloromethane; mp: 121 – 123 °C; H NMR (300 MHz, CDCl3) δ (ppm)
8.50 (d, J = 1.8 Hz, 1H), 8.19 (d, J = 1.8 Hz, 1H), 7.77 (d, J = 8.2 Hz, 2H), 7.68 (d, J =
8.2 Hz, 2H), 5.88 (s, 2H), 3.80 – 3.77 (m, 2H), 3.53 – 3.51 (m, 2H), 3.34 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ (ppm) 146.9, 145.7, 139.2, 136.3, 132.7, 132.0 (q, 2JC-F3 = 32.3
4
1
Hz), 130.3, 125.8 (q, 3JC-F3 = 3.7 Hz), 124.3 (d, JC-F3 = 0.9 Hz), 123.7 (q, JC-F3 = 270.8
Hz ), 115.4, 95.1, 80.0, 72.9, 71.6, 69.6, 59.2; MS (ES+) m/z (%): 454.0 (100) [M+H]+;
HRMS (ESI) calculated for C19H16N3O2F3Br 454.0378 found 454.0375.
6-bromo-3-((2-methoxyethoxy)methyl)-2-(thiophen-3-ylethynyl)-3H-imidazo[4,5-b]-
pyridine (7m): The reaction carried out following procedure D starting from 3Hꢀ
imidazo[4,5ꢀb]pyridine 3a (100 mg, 0.35 mmol) and CuBr.SMe2 (6.46 mg, 0.04 mmol) as
the copper catalyst in a sealed tube afforded 7m (70 mg, 51 % versus 42 % with
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Cu(OAc)2) as a beige solid after flash chromatography followed by recrystallization in a
mixture of cyclohexane/dichloromethane; mp: 99 – 101 °C;1H NMR (300 MHz, CDCl3) δ
(ppm) 8.47 (d, J = 1.8 Hz, 1H), 8.16 (d, J = 1.8 Hz, 1H), 7.82 – 7.74 (m, 1H), 7.37 (dd, J
= 5.0, 3.0 Hz, 1H), 7.32 – 7.26 (m, 1H), 5.85 (s, 2H), 3.81 – 3.78 (m, 2H), 3.54 – 3.51 (m,
2H), 3.35 (s, 3H); 13C NMR (75 MHz, CDCl3) δ (ppm) 146.4, 145.7, 139.9, 136.3, 132.4,
129.9, 126.3, 119.7, 115.1, 92.6, 77.9, 72.8, 71.5, 69.5, 59.2; MS (ES+) m/z (%): 394.0
(100) [M+H]+; HRMS (ESI) calculated for C16H15N3O2SBr 392.0068 found 392.0060.
5-chloro-3-((2-methoxyethoxy)methyl)-2-(naphtalen-2-ylethynyl)-3H-imidazo[4,5-
b]pyridine (8a): The reaction carried out following procedure D starting from 3Hꢀ
imidazo[4,5ꢀb]pyridine 3b (100 mg, 0.41 mmol) and CuBr.SMe2 (8.51 mg, 0.04 mmol) as
the copper catalyst afforded 8a (80 mg, 50 %) as a brown solid after flash
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chromatography; mp: 121 – 123 °C; H NMR (300 MHz, CDCl3) δ (ppm) 8.19 (s, 1H),
7.98 (d, J = 8.3 Hz, 1H), 7.85 (d, J = 8.3 Hz, 3H), 7.64 (d, J= 8.5 Hz, 1H), 7.60 – 7.48 (m,
2H), 7.29 (d, J = 8.3 Hz, 1H), 5.89 (s, 2H), 3.85 – 3.82 (m, 2H), 3.57 – 3.54 (m, 2H), 3.36
(s, 3H); 13C NMR (75 MHz, CDCl3) δ (ppm) 147.3, 134.3, 134.1, 133.7, 133.3, 132.8,
130.0, 128.6, 128.2, 128.0, 127.9, 127.1, 120.1, 117.8, 97.5, 78.5, 72.8, 71.6, 69.5, 59.2;
MS (ES+) m/z (%): 392.1 (100) [M+H]+; HRMS (ESI) calculated for
C22H19N3O2Cl392.1166 found 392.1168.
5-chloro-3-((2-methoxyethoxy)methyl)-2-((4-methoxyphenyl)ethynyl)-3H-imidazo-
[4,5-b]pyridine (8b): The reaction carried out following procedure D starting from 3Hꢀ
imidazo[4,5ꢀb]pyridine 3b (100 mg, 0.41 mmol) and CuBr.SMe2 (8.51 mg, 0.04 mmol)
as the copper catalyst afforded 8b (53 mg, 35 %) as a brown solid after flash
chromatography
followed
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recrystallization
in
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mixture
of
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cyclohexane/dichloromethane; mp: 114 – 116 °C; H NMR (300 MHz, CDCl3) δ (ppm)
7.96 (d, J = 8.1 Hz, 1H), 7.58 (d, J = 8.7 Hz, 2H), 7.29 (s, 1H), 6.92 (d, J = 8.7 Hz, 2H),
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5.84 (s, 2H), 3.85 (s, 3H), 3.83 – 3.77 (m, 2H), 3.58 – 3.48 (m, 2H), 3.35 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ (ppm) 161.2, 147.0, 134.2, 134.1, 130.9, 129.8, 120.4, 119.9,
114.4, 112.5, 97.5, 77.3, 72.7, 71.5, 69.5, 59.2, 55.5; MS (ES+) m/z (%): 372.1 (100)
[M+H]+; HRMS (ESI) calculated for C19H19N3O3Cl 372.1115 found 372.1102.
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6-bromo-7-chloro-3-((2-methoxyethoxy)-methyl)-2-(naphtalen-2-ylethynyl)-3H-
imidazo[4,5-b]pyridine (8c): The reaction carried out following procedure D starting
from 3Hꢀimidazo[4,5ꢀb]pyridine 3c (100 mg, 0.31 mmol) and CuBr.SMe2 (6.41 mg, 0.03
mmol) as the copper catalyst afforded 8c (88 mg, 60 %) as a yellow solid after flash
chromatography
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cyclohexane/dichloromethane; mp: 138 – 140 °C; H NMR (300 MHz, CDCl3) δ (ppm)
8.52 (s, 1H), 8.18 (s, 1H), 7.84 (d, J = 7.6 Hz, 3H), 7.63 (d, J = 8.4 Hz, 1H), 7.59 – 7.48
(m, 2H), 5.89 (s, 2H), 3.85 – 3.78 (m, 2H), 3.56 – 3.50 (m, 2H), 3.35 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ (ppm) 147.4, 146.0, 139.9, 134.4, 134.3, 133.7, 133.4, 132.6, 128.5,
128.1, 127.9, 127.8, 127.1, 117.4, 115.9, 98.3, 78.1, 73.2, 71.5, 69.6, 59.2; MS (ES+) m/z
(%): 472.0 (100) [M+H]+;HRMS (ESI) calculated for C22H18N3O2ClBr 470.0271 found
470.0273.
6-bromo-7-chloro-3-((2-methoxyethoxy)-methyl)-2-((4-methoxyphenyl)ethynyl)-3H-
imidazo[4,5-b]pyridine (8d): The reaction carried out following procedure D starting
from 3Hꢀimidazo[4,5ꢀb]pyridine 3c (100 mg, 0.31 mmol) and CuBr.SMe2 (6.41 mg, 0.03
mmol) as the copper catalyst afforded 8d (55 mg, 39 %) as a brown solid after flash
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chromatography; mp: 117 – 119 °C; H NMR (300 MHz, CDCl3) δ (ppm) 8.52 (s, 1H),
7.58 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 5.85 (s, 2H), 3.85 (s, 3H), 3.80–3.77
(m, 2H), 3.56 – 3.46 (m, 2H), 3.34 (s, 3H); 13C NMR (75 MHz, CDCl3) δ (ppm) 161.4,
147.2, 146.1, 140.3, 134.4, 134.2, 134.2, 115.8, 114.5, 112.1, 98.5, 77.1, 73.1, 71.5, 69.5,
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