Modular Approach to Tricyclic Heterocycles through Copper Catalysis and Functionalization by Palladium-Catalyzed C–H Arylation

Article abstract of DOI:10.1002/ejoc.201700356

A copper-catalyzed Ullman reaction accompanied with oxidative C–N bond formation was used to access tricyclic heterocycles in a one-pot operation by using atmospheric air as the terminal oxidant. This modular synthesis approach was used to synthesize previously known and novel azole-containing heterocycles with different nitrogen position isomers. Fused heterocycles were further functionalized by palladium-catalyzed direct C–H arylation methodology. Various electron-rich and electron-poor functional groups were tolerated in the ortho, meta, and para positions of the aryl bromides.

Full text of DOI:10.1002/ejoc.201700356

A Journal of
Accepted Article
Title: Modular Approach to Tricyclic Heterocycles via Copper Catalysis
and Functionalization with Palladium Catalyzed C-H Arylation
Authors: Esa Tuomo Kumpulainen and Antonia Högnäsbacka
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10.1002/ejoc.201700356
European Journal of Organic Chemistry
COMMUNICATION
Modular Approach to Tricyclic Heterocycles via Copper Catalysis
and Functionalization with Palladium Catalyzed C-H Arylation
Esa T. T. Kumpulainen*[a] and Antonia Högnäsbacka[a]
Abstract: A copper catalyzed Ullman reaction accompanied with
oxidative C-N bond formation is used to access tricyclic heterocycles
in a one pot operation using atmospheric air as the terminal oxidant.
This modular synthesis approach was used to synthesize previously
known and novel azole containing heterocycles with different
nitrogen position isomers. Fused heterocycles were further
functionalized with palladium catalyzed direct C-H arylation
methodology. Various electron rich and electron poor functional
groups were tolerated in ortho-, meta- and para-positions of aryl
bromides.
Introduction
Azoquinazolinones and related fused heterocycles have been
Figure 1. Examples of bioactive compounds containing tricyclic heterocycle
utilized in pharmaceutically interesting inhibitors (Figure 1).[1]
Structural survey revealed that azopyridopyrimidinones were
less common feature and many of the core structures were
previously unknown.[2] The classical synthesis approach to these
heterocycles rely mainly on condensation of suitable coupling
partners to build a fused heterocycle (Scheme 1a). This
skeleton.[1]
approach requires
a
lengthy linear synthesis of key
intermediates which are then condensed with variety of suitable
coupling partners. An alternative approach is based on Ullman
coupling[3] of individual (hetero)arene components followed by
oxidative ring formation (Scheme 1b). These core heterocycles
could be further functionalized with direct C-H activation
techniques (Scheme 1c).[4,5] Together these techniques would
form a diversity orientated modular access to fused heterocycles
in this class.
Copper catalyzed oxidative heteroarene synthesis has
emerged as a new tool synthetic chemists and has gained
recently wide spread interest from the scientific community.[6,7]
Oxidative ring construction of azoquinazolinone type structures
have been previously reported.[8] These methods utilize pure
oxygen as the terminal oxidant which represents a significant
safety risk. The use of pure oxygen under high temperatures
may also lead oxidative side reactions giving complex mixtures
of products.[9] Atmospheric air or nitrogen diluted air would be
preferable terminal oxidants since they would permit safer
operation.
Scheme 1. Comparison of fused heterocycle synthesis techniques.[1,8]
Results and Discussion
We became interested in azopyridopyrimidinones (Table 1, e.g.
compound 1) due to their possible bioequivalence to
azoquinazolinones (e.g. compound 5). The copper catalyzed
oxidative ring formation seemed to be an efficient pathway for
these structures allowing rapid construction of various
structurally related core units. The search for suitable reaction
conditions was initiated with copper(I) iodide catalyzed oxidative
formation of imidazole containing fused heterocycles 1-5 (Table
1). Many of these reactions suffered from poor selectivity due to
[a]
Medicinal Chemistry, Orion Corporation,
Orionintie 1, FI-02200 Espoo, Finland
E-mail: esa.kumpulainen@orion.fi
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201700356
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COMMUNICATION
Table 1. Copper catalyzed synthesis of fused tricyclic heterocycles.
[a] 1 g of 2-chloro-N-alkylnicotinamide used. [b] Oxidative step performed under a balloon of 50 % air / N2. [c] Corresponding bromide starting material used. [d]
No picolinic acid added. [e] 1 eq. imidazole added into the oxidative step to enhance reactivity. [f] Additional 10 mol-% CuI was added into oxidative step due to
poor reactivity.
oxidative decomposition of corresponding Ullman inter-
mediates.[10] Careful control over temperature and reaction time
allowed the synthesis of some of these products (1 and 2) in
good yields (77-88 %) even on a gram scale using atmospheric
air as the terminal oxidant. Other imidazole containing products
3-5 required the use of nitrogen diluted air (< 10 % O2 in N2).
This reduced the amount of oxidative side reactions and gave
moderate to good yields (47-78 %) of heterocycles 3-5. Triazole
was also a good substrate for copper catalysed reaction and
heterocycles 7-10 were obtained in fair to good yields (50-79 %).
Pyrazole reacted sluggishly and product 6 was obtained in low
yield (12 %).
Next we turned our attention to substituted imidazole and
triazole substrates to determine the regiochemical outcome of
the coupling reaction. Typically heteroaryls react from the less
sterically hindered nitrogen in Ullman coupling reactions.[3b] This
indeed turned out to be the case when 4-methyl imidazole was
coupled with 2-chloro-N-methyl-nicotinamide and a 4:1 mixture
of coupling products 11 and 12 were obtained. Arylimidazoles
gave single regioisomers of heterocycles 13-15 in low yields (23-
38 %). Aryltriazoles were good substrates for the coupling
reaction and products 16-18 obtained in moderate yields (33-
58 %) as single regioisomers.
Our previous findings on palladium catalyzed C-H arylation
of (hetero)aryls[11] and the vast literature on C-H activation of
nitrogen fused heteroaryls[12-14] led us to consider further
functionalization of the obtained tricyclic heterocycles. Palladium
catalyzed direct C-H arylation[11b] of heterocycle
1 with
bromobenzene gave monoarylated product 19 in good yield
(Table 2). Structural analysis of 19 with NMR revealed C9-
arylation giving access to different substitution pattern than
found for copper catalyzed reaction in Table 1.[15] The
performance of palladium catalyzed system was evaluated by
testing the reaction with various aryl bromides. Moderate to
good isolated yields (58-80 %) were obtained with para-, meta-
and ortho- substituted aryl bromides containing both electron
rich and electron poor functional groups (products 20-28). Steric
hindrance of methyl ester group in ortho-position resulted in poor
conversion and low yield (product 29, 27 %) even with higher
catalyst loading. Bromopyridine and bromopyrimidine with halide
at meta-position (products 30 and 31) gave poor to good (36-
76 %) yields.
Initially it was assumed that pyridinyl nitrogen in N1-position
of heterocycle 1 might provide the observed regiochemical
outcome via chelation assisted C-H activation (Tables 1 and 2).
In order to clarify this, two other nitrogen isomers of
imidazopyridopyrimidinones (compounds 3 and 4) and
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Table 2. Direct palladium catalyzed C-H arylation of fused heterocycle cores.
[a] 10 mol-% Pd(OAc)2, 20 mol% ethylhexanoic acid, 30 mol-% PCy3. [b] Poor conversion.
imidazoquinazolinone (compound 5) were used as substrates in
the direct C-H arylation reaction. These molecules reacted in a
similar fashion with same regiochemical outcome (products 32-
35). Therefore chelation assistance is not required by these
reactions but cannot be ruled out in the direct C-H arylation of
heterocycle 1.
Triazole containg heterocycles 7 and 10 reacted sluggishly
in the direct C-H arylation reaction and only low yields (23-28 %)
were obtained (Table 2, products 16 and 18). Although the
yields in these reactions were not satisfactory, the palladium
catalyzed direct C-H arylation with commercially abundant aryl
bromides gives more flexibility to the synthesis of similar targets
since the commercial availability of aryltriazoles is rather limited.
isomers.[2] Copper catalyzed oxidative C-N bond forming
reaction utilize atmospheric air or nitrogen diluted air as the
terminal oxidant allows safer operation in elevated temperature
conditions. Heterocyclic cores were further functionalized with
palladium catalyzed direct C-H arylation methodology. Various
functional groups were tolerated in para-, meta- and -ortho
positions of aryl bromides and a diverse set of arylated fused
heterocycles were obtained.
Experimental Section
A typical procedure for copper catalyzed oxidative synthesis of
fused heterocycles (Table 1).
6-Methylimidazo[1,2-a]pyrido[3,2-e]pyrimidin-5(6H)-one (1). To
a
Conclusions
pressure tube was added 2-chloro-N-methylnicotinamide (1.00 g, 5.9
mmol), imidazole (0.80 g, 12 mmol), picolinic acid (0.14 g, 1.2 mmol),
cesium carbonate (1.9 g, 5.9 mmol) and copper(I) iodide (0.22 g, 1.2
mmol). Air atmosphere was removed with nitrogen flow and dry
dimethylsulfoxide (10 mL) was added. The vial was sealed and heated to
100 ºC under vigorous stirring. The reaction was heated for 3.5 h under
In conclusion, an efficient copper catalyzed oxidative synthesis
of various tricyclic heterocycles was developed. The approach
allows rapid construction of previously known fused heterocycles
and novel core structures with different nitrogen position
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10.1002/ejoc.201700356
European Journal of Organic Chemistry
COMMUNICATION
nitrogen atmosphere in order to allow Ullman intermediate to form.
Reaction vessel was uncapped and the reaction mixture was exposed to
atmospheric air. The heating was continued at 100 ºC for 8.5 h. Reaction
mixture was cooled to room temperature. Aqueous 5 % citric acid
solution (30 mL) and dichloromethane (30 mL) were added and resulting
mixture was stirred vigorously until fully soluble. Phases were separated
and the aqueous phase was extracted with dichloromethane (30 mL).
The combined organic phases were washed with brine, dried over
anhydrous sodium sulfate and solvents were evaporated yielding the
crude product as a yellow solid. The crude product was slurried with
refluxing ethyl acetate (10 mL) before being cooled to room temperature
and filtered. Product was dried in 40 °C vacuum oven to give 0.91 g
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[2]
[3]
Reaxys database search done in August 2016. Cores structures of
compounds 3, 8 and 9 in Table 1 were also among the unknown
heterocycles. See supporting information for details.
1
(77 %) of heterocycle 1 as light yellow solids. H NMR (400MHz, CDCl3)
δ 8.74 (dd, J=1.8, 4.8 Hz, 1H), 8.66 (dd, J=1.9, 7.9 Hz, 1H), 7.85 (d,
J=1.8 Hz, 1H), 7.43 (dd, J=4.8, 7.9 Hz, 1H), 7.16 (d, J=1.8 Hz, 1H), 3.77
(s, 1H); 13C NMR (101MHz, CDCl3) δ 159.2, 153.9, 146.1, 143.0, 138.9,
128.8, 121.7, 112.4, 110.5, 29.7; HRMS (ESI-TOF) m/z calcd. for
C10H9N4O [M + H]+ 201.0776, found: 201.0755.
a) F. Ullmann, Chem. Ber. 1903, 36, 2382-2384. b) R. A. Altman, E. D.
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2220.
A typical procedure for direct palladium catalyzed C-H arylation of
fused heterocycles (Table 2).
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6-Methyl-9-phenylimidazo[1,2-a]pyrido[3,2-e]pyrimi-din-5(6H)-one
(19).
A
pressure tube was charged with 6-methylimidazo[1,2-
a]pyrido[3,2-e]pyrimidin-5(6H)-one 1 (50 mg, 0.25 mmol), bromobenzene
(27 µL, 0.25 mmol), anhydrous potassium carbonate (52 mg, 1.5 mmol),
2-ethylhexanoic acid (4 µL, 0.050 mmol), palladium acetate (2.8 mg,
0.025 mmol) and xylene (1.5 mL). Air atmosphere was removed with
nitrogen flow and tricyclohexylphosphine (10.5 mg, 0.075 mmol) was
added, then tube was sealed. Reaction was allowed to stir at room
temperature for 5-15 minutes, then heated to 140 °C and mixed for 18
hours. Reaction was allowed to cool to room temperature, diluted with
dichloromethane (8 mL) and filtered through celite. Solvents were
evaporated under vacuum. Crude product was purified with reverse
phase (C18) column chromatography using 10-100 % MeCN / aqueous
0.1% NH4OH buffer to give 48 mg (70 %) of product 19 as yellow
crystalline solids. 1H NMR (400 MHz, CDCl3) δ 8.68 (dd, J=1.9, 7.8 Hz,
1H), 8.48 (dd, J=1.9, 4.7 Hz, 1H), 7.57 - 7.51 (m, 2H), 7.45 - 7.39 (m, 3H),
7.37 (dd, J=4.7, 7.8 Hz, 1H), 7.08 (s, 1H), 3.83 (s, 3H); 13C NMR (101
MHz, CDCl3) δ 159.1, 152.9, 147.5, 144.0, 138.7, 130.9, 130.2, 129.1,
128.8, 128.1, 127.7, 121.4, 112.7, 29.8; HRMS (ESI-TOF) m/z calcd. for
C16H13N4O [M + H]+ 277.1089, found: 277.1069.
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Acknowledgements
The research leading to these results has received funding from
the Innovative Medicines Initiative Joint Undertaking project
CHEM21 under grant agreement n°115360, resources of which
are composed of financial contribution from the European
Union’s Seventh Framework Programme (FP7/2007-2013) and
EFPIA companies’ in kind contribution.
Keywords: C-H activation • C-C coupling • Copper •
Heterocycles • Palladium
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European Journal of Organic Chemistry
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[10] Stability test of product 5 under used oxidative reactions conditions
revealed that the product itself was not susceptible to decomposition.
Isolated and purified corresponding Ullman intermediate subjected to
same reaction conditions showed similar decomposition pattern as
observed during the one pot procedure.
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Lane, D. Sames, Org. Lett. 2006, 8, 1979-1982. b) A. C. Humphries, E.
Gancia, M. T. Gilligan, S. Goodacre, D. Hallett, K. J. Merchant, S. R.
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S. El Kazzouli, S. Berteina-Raboin, A. Mouaddib, G. Guillaumet, Synlett
2006, 3237-3242. d) R. R. Singhaus, R. C. Bernotas, R. Steffan, E.
Matelan, E. Quinet, P. Nambi, I. Feingold, C. Huselton, A. Wilhelmsson,
[15] For two rare examples of 9-aryl imidazo[1,2-a]quinazolin-5(4H)-ones,
see: R. Murdoch, W. R. Tully, R. Westwood, J. Heterocyclic Chem.
1986, 23, 833-841.
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10.1002/ejoc.201700356
European Journal of Organic Chemistry
COMMUNICATION
COMMUNICATION
Copper and Palladium Catalysis
Esa T. T. Kumpulainen* and Antonia
Högnäsbacka
1 – 5
Modular Approach to Tricyclic
Heterocycles via Copper Catalysis
and Functionalization with Palladium
Catalyzed C-H Arylation
Oxidative copper catalyzed ring construction gives a modular access to tricyclic
heteroaryls. These structures were further substituted using palladium catalyzed
C-H activation together with aryl bromides containing various functional groups.
This article is protected by copyright. All rights reserved.