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Synthesis 2010(1): 136-140  
DOI: 10.1055/s-0029-1217065
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© Georg Thieme Verlag Stuttgart ˙ New York

Straightforward Functionalization of 3,5-Dichloro-2-pyrazinones under Simultaneous Microwave and Ultrasound Irradiation

Davide Garellaa, Silvia Tagliapietraa, Vaibhav P. Mehtab, Erik Van der Eyckenb, Giancarlo Cravotto*a
a Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via P. Giuria 9, 10125 Torino, Italy
Fax: +39(011)6707687; e-Mail: giancarlo.cravotto@unito.it;
b Laboratory for Organic and Microwave-Assisted Chemistry, Department of Chemistry, Katholieke Universiteit Leuven, Celestijnenlaan 200F, 3001 Leuven, Belgium

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Publication History

Received 6 July 2009
Publication Date:
26 October 2009 (online)

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Abstract

Heck reactions and Suzuki-Miyaura cross-couplings with relatively poorly reactive 3,5-dichloro-2-pyrazinones were studied at the same temperature under conventional heating, dielectric heating (MW) and simultaneous MW/US irradiation. This comparative study showed a synergic effect of combined MW and US irradiation resulting in a much higher reaction yield, at the same time avoiding side reactions and partial degradation that is otherwise observed under conventional heating.

Key words

pyrazinones - ultrasound - microwaves - simultaneous irradiation - Heck reaction - Suzuki cross-coupling

The screening of compound libraries in order to identify useful modulators of biological systems is a fundamental process in chemical biology studies. Libraries containing a broad range of compounds are particularly valuable for screening purposes. [¹] In order to obtain such large library sets, fast and efficient procedures are required for chemical bond transformations. Often, compounds are synthesized using prolonged conventional heating that results in the formation of side products or decomposition. The current drive towards cleaner chemistry [²] and chemical engineering has spurred a search for more selective and energy-saving protocols, prompting a reconsideration of metal-catalyzed processes that are nowadays intensively used in organic syntheses.

Two non-conventional activation tools, microwaves (MW) and power ultrasound (US), have been shown to substantially reduce reaction times, increase product yields and enhance product purity by reducing or even eliminating side reactions. Microwave-assisted chemistry has blossomed into a useful technique for a plethora of applications in organic synthesis and transformations. [³] The application of power US in chemical processes is one of a number of intensification technologies that have undergone wide-ranging development over the past two decades. [4]

The driving forces for this trend are manifold, although, as emphasized above, an important factor is surely the increasing demand for environmentally safe technologies that minimizes the production of waste. Energy input by US does promote cleaner reactions by improving product selectivities and yields, as well as by increasing product recovery and purity through, for instance, sono-crystallization. [5] In this context, the specific advantages of MW and power US may become additive or synergic when they are used in combination. [6] [7]

Over the years, pyrazinone chemistry [8] has been used in medicinal and peptidomimetic [9] chemistry in a number of different ways. The 2-(1H)-pyrazinones readily undergo a range of reactions, such as cycloaddition-elimination reactions with acetylenes, generating pyridines and pyridones, α-carbolines, β-carbolines and bicyclic compounds, which are valuable building blocks for the synthesis of β-turn mimics. [9] Many of these new compounds, as well as the substituted pyrazine-2-(1H)-ones themselves, display important biological activity, for example as non-nucleoside HIV-1 reverse-transcriptase inhibitors (NNRTI’s), [¹0] µ-opioid receptor agonists [¹¹] and selective tissue factor VIIa inhibitors. [¹²] Moreover, the pyrazinone skeleton is a central core in various natural products such as Dragmacidin, Flavacol and Ma’edamine. [¹³] We have previously demonstrated several MW-assisted transition-metal catalyzed procedures for the decoration of the pyrazinone scaffold [¹4] as an alternative privileged structure. Taking full advantage of these existing conventional MW-assisted methods for the decoration of the pyrazinones, we have also elaborated solid-phase versions of these reactions. [¹5] A detailed study has been carried out on the concept of ‘traceless linking’ of 2-(1H)-pyrazinones applying MW irradiation. [¹6] Compernolle et al. investigated palladium-catalyzed Suzuki and Heck reactions on 3,5-dichloropyrazinones and showed that the 5-chloro atom was inert towards these cross-couplings; for this reason, it was first trans-halogenated via a reduction/bromination (or iodination) sequence. [¹7] During the course of our studies on the effect of MW [¹8] [¹9] and US [²0] [²¹] irradiation in transition-metal catalyzed cross-coupling reactions, we showed the beneficial effects of simultaneous MW and US irradiation and developed conditions that allowed palladium-catalyzed reactions to proceed with an exceptionally low catalyst load. [²²]

With our previous experience in synthetic protocols for combined MW/US irradiation, [²¹-²³] our aim was to investigate the efficiency of this technique for the selective functionalization of 3,5-dichloro-2-(1H)-pyrazinones. Under such conditions, these reactions are usually strongly accelerated, and lead to improved yields by reducing the extent of degradation that can arise from prolonged heating. [²4] [²5] For strict temperature control and in order to prevent superheating that would decrease cavitation, simultaneous MW/US irradiation requires an efficient cooling system. This can be achieved by circulating a microwave-transparent refrigerated fluid such as Galden® (Solvay-Solexis), which is a perfluoropolyether with a high boiling point and a low viscosity. The temperature was monitored with a fiber-optic thermometer inserted in the flask (Figure  [¹] ).

Figure 1 Simultaneous US/MW irradiation apparatus (horn made of PEEK®)

MW/US-assisted C-C couplings can usually be performed with ligand-free palladium catalysts - typically palladium salts and even palladium on charcoal. [²²] [²6] We can speculate that the formation of palladium nano-clusters is much faster so they are immediately available for the oxidative addition.

First we studied the Heck reaction of 3,5-dichloro-2-(1H)-pyrazinones (1-3) with styrene, carrying out the reaction using three different techniques, namely: conventional heating, MW irradiation, and simultaneous MW/US irradiation (Scheme  [¹] , Table  [¹] ). In all cases, reactions were carried out in dimethylacetamide (DMA) under nitrogen atmosphere using palladium acetate in the presence of potassium carbonate and tetrabutylammonium bromide (TBAB). Upon stirring under conductive heating, in spite of a complete conversion after 90 minutes, the yield was generally low due to partial degradation and the formation of by-products. In contrast, when the reaction was carried out under MW irradiation or, better, under MW/US irradiation, yields were greatly improved (Table  [¹] , entries 1-3). A complete conversion was observed after only 20 minutes with excellent reproducibility (Scheme  [¹] ).

Scheme 1 Typical procedure for Heck reaction (Table 1, entries 1-3)

For entry 2, the reaction was also carried out under US irradiation alone working with the same probe (horn in PEEK®, 21.2 kHz, 50 W) and at the same temperature (120 ˚C) in a thermostatted reactor. Complete conversion was observed after 20 minutes; however, these conditions resulted in a lower yield (close to 60%).

The same 3,5-dichloro-2-pyrazinones (1-3) were subjected to Suzuki-Miyaura cross-coupling with phenylboronic acid in dimethylacetamide using a very low loading (0.005 mmol) of tetrakis(triphenylphosphine) palladium as catalyst and cesium carbonate as base (Scheme  [²] , Table  [¹] entries 4-6). Once again, we compared conventional heating, MW, and MW/US irradiation at the same temperature of 120 ˚C. Yields increased from 7-14% under conventional heating to 63-86% under MW/US irradiation. The same differences were observed using Pd(OAc)2 (1 mol%), albeit with slightly poorer yields.

Scheme 2 Typical procedure for Suzuki cross-coupling (entries 4-6)

Table 1 Reaction Conditions for Heck and Suzuki Couplings
Entry Starting material Product
Conventional heating
 MW 80W
 MW/US
40/30W
Time (min) Yield (%) Time (min) Yield (%) Time (min) Yield (%)
1a 1 4

90 42 20 61 20 80
2a 2 5

90 38 20 69 20 91
3a 3 6

90 31 20 60 20 90
4b 1 7

15  8 15 25 15 63
5b 2 8

15 14 15 53 15 86
6b 3 9

15  7 15 42 15 81
a Heck reaction (see Scheme  [¹] ). b Suzuki reaction (see Scheme  [²] ).

In conclusion, the Heck reaction and Suzuki couplings have been performed on three different 3,5-dichloro-2-(1H)-pyrazinones with low catalyst loads under simultaneous MW/US irradiation to give much faster and cleaner reactions. It emerged clearly that, compared to conventional heating, both MW and, particularly, MW/US irradiation were beneficial for the efficient chemical decoration of pyrazinones. Due to the optimal heat- and mass-transfer, simultaneous MW/US irradiation, greatly improved the kinetics and yields of these chemical modifications.

Commercially available reagents and solvents were used without further purification. Reactions were monitored by TLC on Merck 60 F254 (0.25 mm) plates, which were visualized by UV inspection. MW-promoted reactions were carried out in a professional oven from MicroSYNTH-Milestone (Italy). This was also used for combined MW/US irradiation after a probe equipped with a PEEK® horn was inserted into it. The purification was performed by flash-chromatography on a silica column (CombiFlash Rf® Teledyne ISCO). NMR spectra were recorded at 25 ˚C on a Bruker 300 Avance (300 MHz for ¹H) spectrometer. Chemical shifts (δ) were calibrated against residual proton and carbon resonances of the solvent CDCl3 (δ = 7.26 ppm), and are given in ppm; coupling constants are given in Hz. Low-resolution mass spectra were recorded on a Finnigan-MAT TSQ70 instrument using chemical ionization (CI) with isobutane as reactant gas. IR spectra were recorded with a Shimadzu FT-IR 8001 spectrophotometer.

Heck Reaction (Entries 1-3); General Procedure

A mixture of pyrazinone (1-3), styrene (1.3 equiv), TBAB (1 equiv), K2CO3 (1.5 equiv) and Pd(OAc)2 (1% mol) in DMA (10 mL) was placed in a three-necked round-bottomed flask and either heated or irradiated with MW or MW/US (average power 80W with MW and 40/30W with MW/US) under nitrogen at 120 ˚C for 20 min. The temperature was measured with an optical-fiber thermo­meter, and the reaction was monitored by TLC. The mixture was washed with H2O and EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, concentrated under vacuum and purified by flash chromatography over silica gel column (hexane-EtOAc, 8:2).

Suzuki Cross-Coupling (Entries 4-6) General Procedure

A mixture of the pyrazinone (1-3), phenylboronic acid (1.05 equiv), Cs2CO3 (0.75 mmol) and Pd(PPh3)4 (0.005 mmol) in DMA (5 mL), was placed in a three-necked flask and either heated or irradiated with MW and/or US (average power 80W with MW and 40/30W with MW/US) under nitrogen at 120 ˚C for 15 min. The reaction was monitored by TLC. The mixture was washed with H2O and EtOAc. The organic layer was washed with brine solution, dried over anhydrous MgSO4, concentrated under vacuum and purified by flash chromatography over silica gel (hexane-EtOAc, 8:2).

5-Chloro-1-(4-methoxybenzyl)-3-styrylpyrazin-2-(1 H )-one (4)

Pale-yellow crystals; mp 120 ˚C.

FT-IR (KBr): 2954, 2840, 1655, 1612, 1574, 1514, 1304, 1250, 1177, 1101, 1032, 976, 908, 820, 746 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 8.05 (d, J = 16.2 Hz, 1 H), 7.63 (d, J = 9.3 Hz, 2 H), 7.55 (d, J = 16.2 Hz, 1 H), 7.38-7.26 (m, 5 H), 7.07 (s, 1 H), 6.92 (d, J = 9.0 Hz, 2 H), 5.04 (s, 2 H), 3.82 (s, 3 H).

¹³C NMR (75 MHz, CDCl3): δ = 160.1, 154.7, 152.0, 138.9, 136.3, 130.4, 129.5, 128.9, 128.0, 127.1, 126.3, 123.9, 121.6, 114.7, 55.4, 52.2.

MS (CI, i-Bu): m/z (%) = 353/355 [MH+].

Anal. Calcd for C20H17ClN2O2: C, 68.09; H, 4.86; N, 7.94. Found: C, 68.14; H, 4.90; N, 7.97.

5-Chloro-1-(4-methoxybenzyl)-6-(4-methoxyphenyl)-3-styrylpyrazin-2-(1 H )-one (5)

Yellow crystals; mp 147 ˚C.

FT-IR (KBr): 2932, 2836, 1651, 1609, 1512, 1337, 1294, 1250, 1177, 1032, 974, 916, 837, 745, 691 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 8.11 (d, J = 16.2 Hz, 1 H), 7.66-7.58 (m, 3 H), 7.38-7.35 (m, 3 H), 7.08 (d, J = 8.7 Hz, 2 H), 6.96 (d, J = 8.7 Hz, 2 H), 6.85 (d, J = 8.7 Hz, 2 H), 6.75 (d, J = 8.7 Hz, 2 H), 5.07 (s, 2 H), 3.88 (s, 3 H), 3.77 (s, 3 H).

¹³C NMR (75 MHz, CDCl3): δ = 160.8, 159.3, 155.6, 150.5, 138.3, 136.6, 136.4, 131.2, 129.4, 129.1, 128.9, 128.0, 127.8, 127.8, 123.5, 122.1, 114.4, 114.0, 55.5, 55.4, 49.6.

MS (CI, i-Bu): m/z (%) = 458/460 [MH+].

Anal. Calcd for C27H23ClN2O3: C, 70.66; H, 5.05; N, 6.10. Found: C, 70.71; H, 5.09; N, 6.16.

6-Benzyl-5-chloro-1-(4-methoxybenzyl)-3-styrylpyrazin-2-(1 H )-one (6)

Yellow crystals; mp 184 ˚C.

FT-IR (KBr): 2997, 2926, 2832, 1645, 1624, 1543, 1512, 1458, 1341, 1248, 1176, 1037, 955, 818, 754, 721, 698 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 8.11 (d, J = 16.2 Hz, 1 H), 7.66 (d, J = 6.9 Hz, 2 H), 7.59 (d, J = 16.2 Hz, 1 H), 7.38 (m, 6 H), 7.15 (d, J = 6.9 Hz, 2 H), 7.10 (d, J = 8.7 Hz, 2 H), 6.89 (d, J = 6.9 Hz, 2 H), 5.13 (s, 2 H), 4.15 (s, 2 H), 3.81 (s, 3 H).

¹³C NMR (75 MHz, CDCl3): δ = 159.5, 156.0, 149.9, 138.3, 136.5, 135.0, 134.9, 129.5, 129.4, 128.9, 128.6, 128.0, 127.9, 127.6, 127.1, 122.0, 114.6, 55.4, 48.0, 35.6.

MS (CI, i-Bu): m/z (%) = 442/444 [MH+].

Anal. Calcd for C27H23ClN2O2: C, 73.21; H, 5.23; N, 6.32. Found: C, 73.29; H, 5.20; N, 6.27.

5-Chloro-1-(4-methoxybenzyl)-3-phenylpyrazin-2-(1 H )-one (7)

Pale-yellow crystals; mp 113 ˚C.

All the spectroscopic data were in agreement with those published. [²5]

5-Chloro-1-(4-methoxybenzyl)-6-(4-methoxyphenyl)-3-phenylpyrazin-2-(1 H )-one (8)

Yellow crystals; mp 179 ˚C.

FT-IR (KBr): 3215, 2932, 2836, 1603, 1512, 1441, 1350, 1340, 1308, 1252, 1181, 1088, 1024, 760, 698, 637 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 8.47-8.41 (m, 2 H), 7.48-7.45 (m, 3 H), 7.11 (d, J = 8.7 Hz, 2 H), 6.97 (d, J = 8.7 Hz, 2 H), 6.87 (d, J = 8.7 Hz, 2 H), 6.74 (d, J = 8.7 Hz, 2 H), 5.11 (s, 2 H), 3.89 (s, 3 H), 3.77 (s, 3 H).

¹³C NMR (75 MHz, CDCl3): δ = 160.8, 159.2, 155.4, 150.8, 135.7, 132.8, 131.1, 130.6, 129.4, 129.1, 128.3, 128.1, 127.7, 123.4, 114.4, 114.0, 55.5, 55.4, 49.8.

MS (CI, i-Bu): m/z (%) = 432/434 [MH+].

Anal. Calcd for C25H21ClN2O3: C, 69.36; H, 4.89; N, 6.47. Found: C, 69.44; H, 4.97; N, 6.59.

6-Benzyl-5-chloro-1-(4-methoxybenzyl)-3-phenylpyrazin-2-(1 H )-one (9)

Yellow crystals; mp 133 ˚C.

FT-IR (KBr): 2997, 2924, 1646, 1553, 1512, 1285, 1252, 1177, 1028, 955, 714, 689 cm-¹.

¹H NMR (300 MHz, CDCl3): δ = 8.48-8.41 (m, 2 H), 7.48-7.46 (m, 3 H), 7.42-7.27 (m, 3 H), 7.18 (d, J = 6.6 Hz, 2 H), 7.12 (d, J = 8.7 Hz, 2 H), 6.88 (d, J = 6.6 Hz, 2 H), 5.17 (s, 2 H), 4.21 (s, 2 H), 3.81 (s, 3 H).

¹³C NMR (75 MHz, CDCl3): δ = 159.5, 155.7, 150.1, 136.2, 135.1, 134.8, 130.6, 129.5, 129.3, 128.3, 128.0, 127.7, 127.2, 114.6, 55.5, 48.2, 35.7.

MS (CI, i-Bu): m/z (%) = 416/418 [MH+].

Anal. Calcd for C25H21ClN2O2: C, 72.02; H, 5.08; N, 6.72. Found: C, 72.10; H, 5.22; N, 6.83.

Acknowledgment

The combined US/MW reactor was developed in collaboration with Danacamerini sas (Torino, Italy). Regione Piemonte and the University of Torino are gratefully acknowledged for financial support (Project NanoIGT 2009).

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Figure 1 Simultaneous US/MW irradiation apparatus (horn made of PEEK®)

Scheme 1 Typical procedure for Heck reaction (Table 1, entries 1-3)

Scheme 2 Typical procedure for Suzuki cross-coupling (entries 4-6)