Direct arylation of imidazo[1,5-a]azines through ruthenium and palladium catalysis

Article abstract of DOI:10.1002/ejoc.201403268

The regioselective Ru^II-catalyzed direct ortho-arylation of C- 3 aryl-substituted imidazo[1,5-a]azines with (hetero)aryl halides was investigated. The employment of Ru^II and Pd^II catalysts in the same flask resulted in two sequential and distinct C-H bond arylations, which allowed the rapid synthesis of highly conjugated compounds.

Full text of DOI:10.1002/ejoc.201403268

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201403268
Direct Arylation of Imidazo[1,5-a]azines Through Ruthenium and Palladium
Catalysis
Daniela Sustac Roman,[a] Valentin Poiret,[a] Guillaume Pelletier,[a] and André B. Charette*[a]
Keywords: Homogeneous catalysis / Ruthenium / Palladium / Arylation / Nitrogen heterocycles
The regioselective RuII-catalyzed direct ortho-arylation of C-
lysts in the same flask resulted in two sequential and distinct
3 aryl-substituted imidazo[1,5-a]azines with (hetero)aryl hal- C–H bond arylations, which allowed the rapid synthesis of
ides was investigated. The employment of RuII and PdII cata- highly conjugated compounds.
interest in imidazo[1,5-a]azines, we report herein a catalytic
Introduction
and regioselective C–H arylation strategy of the C-2Ј/C-1
Bridgehead nitrogen-containing bicyclic aromatic
positions to provide highly functionalized substrates.
scaffolds represent a distinguished class of pharmacoph-
ores, as they often qualify as potent purine and deoxy-
adenosine bioisosteres.[1] In recent years, intensified syn-
thetic efforts have been dedicated toward finding general
strategies for their assembly and functionalization.[2] In par-
ticular, compounds containing a “pyridine-fused” portion
display pertinent biological activities,[3] but oftentimes the
ease of their synthesis is hampered because of increased
numbers of steps or limited bulk accessibility of starting
materials.[4] In the last years, the medicinal chemistry com-
munity has associated an exponential number of diversely
decorated imidazoazine-type structures to drug leads
possessing significant anticancer, anti-HIV, and anti-
inflammatory properties.[5] Among these, the promising
MEK-inhibitor and antineoplastic agent GDC-0623
(Genentech), containing an imidazo[1,5-a]pyridine unit, is
currently an active phase I clinical candidate for the treat-
ment of cancer.[6] In addition, many of the π-conjugated
imidazo[1,5-a]azine structures have been shown to exhibit
high fluorescence levels[7] and are constituents of some or-
ganic light-emitting diodes.[8]
Previous work in our laboratories on heteroarene synthe-
sis and functionalization[9] led to the development of a Pd-
catalyzed direct functionalization/cyclization sequence of
N-iminopyridinium ylides to provide a broad range of pyr-
azolo[1,5-a]pyridines.[10] Of late, we reported a Bischler–
Napieralski-type cyclization mediated by triflic anhydride
Scheme 1. Synthesis and functionalization of imidazo[1,5-a]azines;
Phen = phenanthroline, DMA = dimethylacetamide.
(Tf2O) to access polysubstituted imidazo[1,5-a]azines
(Scheme 1, a).[11] Recognizing the wide applications and
Early arylation strategies of imidazo[1,5-a]pyridines in-
volved a two-step sequence: halogenation of either the C-3
or C-1 position, followed by cross-coupling.[5c,7a] The atom-
economical Pd-catalyzed direct arylation of the C-3 posi-
tion was reported by the Gevorgyan and Murai research
groups (Scheme 1, b).[12] In this context, the latter group
applied a highly reactive Pd–phenanthroline cationic com-
[a] Centre in Green Chemistry and Catalysis, FAS-Department of
Chemistry, Université de Montréal,
P.O. Box 6128, Station Downtown, Montréal, Québec, H3C
3J7, Canada
E-mail: andre.charette@umontreal.ca
http://charette.corg.umontreal.ca
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403268.
Eur. J. Org. Chem. 2015, 67–71
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
67

D. Sustac Roman, V. Poiret, G. Pelletier, A. B. Charette
SHORT COMMUNICATION
plex for sequential arylations of imidazo[1,5-a]pyridines.[12b] less reactive than the bromide or chloride, consistent with
However, other types of direct functionalization of these previous reports.[17] In comparison, meta-substitution pro-
compounds are scant in the literature.[13]
vided the monoaryl products (see compounds 2b–d) in
A distinct strategy for the diversification of compounds yields of 51–87% (Table 1, entries 2–4). Upon employing 3-
of type 1 was envisioned. Given the plethora of methodolo- (3Ј-methoxy)phenylimidazo[1,5-a]pyridine (1c) as the reac-
gies that utilize nitrogen-based chelating groups for activa- tant, a significant amount of diaryl product (see compound
ting C–H bonds,[14] we sought to take advantage of the 3c) was isolated (22% yield; Table 1, entry 3). The second
imidazo[1,5-a]pyridine functionality to selectively direct a arylation at the more sterically hindered ortho C–H position
transition metal to the ortho position of the C-3 aryl sub- may be a result of the secondary directing group effects of
stituent. In the current study, we elected to use a previously the methoxy substituent.[20] Excellent yields were obtained
reported ruthenium(II)/carboxylate catalyst combination, a if the aryl bromide was employed as the limiting agent for
well-established and attractive method for C–H functionali- substrates 1b–d.[21] However, para substitution led to the
zation (Scheme 1, c).[15,16] The mode of action of RuII is formation of two products, with 2.5 or 2:1 selectivity (2e–
similar to that of PdII, in terms of enabling concerted met- g/3e–g; Table 1, entries 5–7). In contrast, ortho-substitution
alation–deprotonation (CMD) reaction pathways, usually provided the corresponding monoaryl products in 63%
mediated by either a ligand at the metal center or a base.[17] yield (see compound 2h; Table 1, entry 8) and 57% yield
However, the Ru-catalyzed process can be divergent by its (see compound 2i; Table 1, entry 9). In the case of 3-(1-
site selectivity, and thus it complements the previously de- naphthyl)-substituted 1i, 19% yield of product 3i containing
veloped Pd-catalyzed arylation.[12] The latter fact allowed an unexpected second arylation was isolated. An imid-
for the development of sequential Ru- and Pd-catalyzed azo[1,5-a]pyridine containing a 2-naphthyl substituent (see
multiple arylations in one pot.
compound 1j) reacted sluggishly, even if an excess amount
of imidazoazine (1j) was employed (Table 1, entry 10). Fi-
nally, quinolone 1k provided solely product 2k in 66% yield
(Table 1, entry 11). As a general trend, the product distri
Results and Discussion
To assess our hypothesis, a deuterium-exchange study[15a] bution observed can be correlated to the steric and elec-
was initially performed on substrate 1a in the presence or tronic influence of the C-3 aryl group of the starting hetero-
absence of Ru as the catalyst (Scheme 2). The C-2Ј position cycle. Imidazo[1,5-a]azines possessing electron-neutral and
exhibited 90% D incorporation, whereas the C-1 position electron-withdrawing substituents usually provided better
exhibited 70% D incorporation.[18] The result confirmed yields and selectivities than imidazo[1,5-a]azines possessing
the hypothesis that RuII could be a potential catalyst for electron-donating substituents.
the arylation of 1a at the desired C-2Ј position. After a
To enlarge the scope of the method, the coupling partner
short optimization, conditions based on Ackermann’s was next explored by employing meta- and para-substituted
work[15,17c] were found ideal for the coupling with aryl hal- imidazo[1,5-a]pyridines (Table 2). The reaction tolerated a
ides {5 mol-% [RuCl2(p-cymene)]2, 30 mol-% 2,4,6-trimeth- variety of useful functional groups such as trifluoromethyl,
ylbenzoic acid (MesCO2H), 2 equiv. K2CO3, in toluene, at fluoride, ester, amide, and methoxy (Table 2, entries 1–4, 7–
130 °C}.[19] Interestingly, no Ru-catalyzed arylation of the 9). Heteroaryl bromides could also be employed as cross-
C-1 position was ever observed during the optimization or coupling partners in very good yields: yields of 77 and 81%
the subsequent work.
were obtained upon using 1.2 equiv. 2-bromothiophene and
The generic optimal conditions were applied to the aryl- 5-bromo-N-methylindole as reactants (Table 2, entries 5
ation of diverse imidazo[1,5-a]azines with 4-bromoaceto- and 6).
phenone as the common coupling partner (Table 1). In the
To take advantage of the site-selective complementary re-
absence of any substitution on the aryl moiety, a mixture activities of PdII and RuII with imidazo[1,5-a]azines, a se-
of mono (see compounds 2) and diaryl (see compounds 3) quential diarylation with the two metals was conducted in
products was obtained (Table 1, entry 1). In the presence of one pot.[22] After completion of the Ru-catalyzed direct
an excess amount (3 equiv.) of the coupling partner, the di- arylation with 4-bromo-1-(trifluoromethyl)benzene and
[23]
aryl product (see compound 3a) was solely isolated (77% imidazo[1,5-a]pyridine (1b), Pd(phen)2(PF6)2
(5 mol-%),
yield). The corresponding chloro- and iodoacetophenones Cs2CO3 (2 equiv.), and the corresponding aryl iodide were
were also screened, and the aryl iodide was found to be simply added to the reaction flask, and the mixture was
Scheme 2. Deuterium-exchange experiments.
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Direct Arylation of Imidazo[1,5-a]azines
Table 1. Scope of the imidazo[1,5-a]azines.
Table 2. Scope of the aryl halide partner.
[a] Conditions: 1 (0.4 mmol), aryl halide (0.48 mmol), MesCO2H
(0.12 mmol), [RuCl2(p-cymene)]2 (0.02 mmol), K2CO3 (0.8 mmol),
PhMe (2 mL), 130 °C, Ar, 15 h, yields of isolated products after
column chromatography are given. [b] Yield in parentheses for the
reaction with 1e (2 equiv.) and 3-bromoanisole (1 equiv.).
with 4-bromoacetophenone (44%), whereas the corre-
sponding aryl chloride was significantly less reactive (9%).
Reversing the order of addition of the aryl halides was also
suitable; in that case 4d was isolated in 51% yield. The se-
quential addition of 4-bromoacetophenone and 4-iodo-
toluene provided 4e in 42% yield. The yield for the coupling
of 4-iodotoluene was much improved (83%, see product 4f)
if 1-bromo-4-fluorobenzene was employed in the Ru reac-
tion. A good yield for the one-pot protocol was also ob-
tained upon employing 4-iodobenzene in the Pd-catalyzed
reaction (70%, see product 4g). The products were readily
separated by conventional chromatography purification.
[a] Conditions: 1 (0.4 mmol), 4-bromoacetophenone (0.48 mmol),
MesCO2H (0.12 mmol), [RuCl2(p-cymene)]2 (0.02 mmol), K2CO3
(0.8 mmol), PhMe (2 mL), 130 °C, Ar, 15 h, yields of isolated prod-
ucts after column chromatography are given. [b] 4-Bromoaceto-
phenone (3 equiv.) was added. [c] With 4-chloroacetophenone.
Conclusions
To conclude, it was established that imidazo[1,5-a]azines
[d] With 4-iodoacetophenone. [e] Yield in parentheses for the reac- can act as directing groups in site-selective Ru-catalyzed
tion with 4-bromoacetophenone (1 equiv.) and 1 (2 equiv.).
ortho-arylations. Whereas selectivity of the transformation
was mostly dictated by the sterics and electronics of the
stirred for the given time under an atmosphere of Ar at starting 3-arylimidazo[1,5-a]azine, a variety of (hetero)aryl
130 °C (Table 3).[24] 4-Iodoanisole and 4-fluoroiodobenzene bromides, chlorides, and iodides were tolerated as coupling
provided corresponding C-2Ј/C-1 bisarylated products 4a partners. The rapid synthesis of highly conjugated hetero-
and 4b in good yields, but 4-iodoacetophenone reacted cycles was enabled by a sequential, one-pot, multiple aryl-
poorly (see product 4c, 23%). A better yield was obtained ation reaction by employing RuII and PdII as catalysts.
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D. Sustac Roman, V. Poiret, G. Pelletier, A. B. Charette
SHORT COMMUNICATION
Table 3. Sequential one-pot arylation.[a]
Acknowledgments
This work was supported by the Universite de Montreal, the Natu-
ral Sciences and Engineering Research Council of Canada
(NSERC), the Canada Research Chair Program, and the Canada
Foundation for Innovation. D. S. R. and G. P. would like to thank
NSERC for CGS scholarships.
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[a] Conditions: 1b (0.2 mmol), Ar1Br (0.24 mmol), MesCO2H
(0.06 mmol), [RuCl2(p-cymene)]2 (0.01 mmol), K2CO3 (0.4 mmol),
PhMe (1 mL), 130 °C, Ar, 6 or 16 h, then Pd(phen)2(PF6)2
(0.01 mmol), Cs2CO3 (0.4 mmol), Ar2X (0.24 mmol), 130 °C, Ar,
6–24 h. In some cases, monoaryl product 2 was also recovered.
[b] Contained about 8% unknown impurity. [c] Compound 2b was
not isolated, but trace amounts of other byproducts were observed
by LC–MS analysis (see the Supporting Information).
Experimental Section
Typical Procedure for Ru-Catalyzed Direct Arylation: A microwave
vial (previously kept in an oven and cooled to room temp. under
an atmosphere of argon) fit with a stir bar was charged with the
corresponding imidazopyridine (0.4 mmol, 1.0 equiv.), 2,4,6-tri-
methylbenzoic acid (0.12 mmol, 0.3 equiv.), and the aryl bromide
(0.48 mmol, 1.2 equiv.), if solid. The vial was then placed in a glove
box and dichloro(p-cymene)ruthenium dimer (0.02 mmol,
0.05 equiv.) and potassium carbonate (0.8 mmol, 2.0 equiv.) were
added. The vial was crimped and taken out of the glove box. The
aryl bromide (0.48 mmol, 1.2 equiv.), if liquid, was added by
syringe, followed by dry toluene (2 mL). The mixture was stirred
at 130 °C for 15 h. Then, the mixture was cooled to room tempera-
ture and filtered through a pad of silica and Celite, rinsing with
EtOAc (15–20 mL). The organic layer was washed with a solution
of saturated aqueous K2CO3 (15 mL) and water (15 mL). The
aqueous layer was extracted with EtOAc (2ϫ 10 mL). The com-
bined organic layer was washed with brine (10 mL), dried
(Na2SO4), and concentrated in vacuo. The resulting residue was
purified by flash chromatography.
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Received: September 26, 2014
Published Online: November 21, 2014
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