Regioselective Suzuki-Miyaura Reaction: Application to the Microwave-promoted Synthesis of 4,7-Diarylquinazolines

New diarylquinazolines displaying pharmaceutical potential were synthesized in high yields from 4,7-dichloro-2-(2-methylprop-1-enyl)-6-nitroquinazoline by using microwave-promoted regioselective Suzuki-Miyaura cross-coupling reactions.


Introduction
In 1979, Suzuki and Miyaura introduced organoboron reagents into the realm of cross-coupling chemistry, by demonstrating a palladium-catalyzed reaction of 1-alkenylboranes with aryl and alkynyl halides [1,2]. Since its discovery, this reaction, which is now referred to as the Suzuki-Miyaura reaction, has seen significant advancement and has become one of the most powerful carbon-carbon bond forming methods in organic synthesis [3][4][5][6]. The process has important advantages including functional group compatibility, low toxicity of reagents and intermediates, easy availability of boron derivatives, high thermal stability and good tolerance toward oxygen and aqueous solvents. Recently, organic chemists have turned their work to the application of this reaction to the synthesis of more complex molecules, by using successive Suzuki-Miyaura cross coupling reactions with substrates OPEN ACCESS containing two or more possible reactive sites. One of the solutions to obtain the desired crosscoupling products in a selective manner, by assembling such multi-functionalized compounds, is to favor one of the possible reaction sites [7,8]. Herein, we will describe a regioselective method based on the modulation of the reaction conditions.
Quinazoline is an important molecular scaffold due to the large variety of pharmacological properties associated with derivatives based on this heterocyclic system [9]. Especially, their importance as selective anticancer chemotherapy agents appears unparalleled and attracts the attention of many pharmaceutical research teams worldwide [10][11][12][13]. Focusing on quinazoline substrates, our group also quite recently described the preparation of new 2-substituted-quinazoline derivatives which exhibit original antiplasmodial properties [14][15][16].
In other respects, microwaves, as a non-conventional source of energy, have become a very popular and useful technology in organic chemistry [17]. The main attraction of using microwaves is the possibility of achieving short reaction times in cleaner systems [18][19][20], even under solventless conditions [21,22]. Microwave irradiation is a simple, rapid and effective method for transferring energy to a polar reaction medium [23]. Consequently, microwave irradiation has been widely applied in organic synthesis, including C-C cross-coupling reactions [24,25].

Results and Discussion
The synthesis of the starting material, 4,7-dichloro-2-(2-methylprop-1-enyl)-6-nitroquinazoline (5), is presented in Scheme 1. The global synthesis strategy was developed in our research group for the preparation of closely related analogs [30]. Compound 5 was obtained from commercial 2-amino-4chlorobenzonitrile in good yield after five steps, under microwave irradiation. The first step is the condensation between 2-amino-4-chlorobenzonitrile and chloroacetyl chloride, followed by intramolecular cyclisation, to give product 2 in 67% yield [31]. Then, nitration at the 6 position gave the expected product 3 (74% yield), followed by a S RN 1 reaction with the lithium salt of 2nitropropane [32,33] leading to the ethylenic derivative 4 (76% yield). Finally, a microwave-assisted chlorination reaction using phosphorus oxychloride in the presence of N,N-diethylaniline gave product 5, bearing two chlorine atoms in positions 4 and 7 (87% yield). The 4,7-dichloro-2-(2-methylprop-1-enyl)-6-nitroquinazoline (5) was engaged in a double Suzuki-Miyaura coupling study with the purpose of identifying reaction conditions which would provide regioselectivity between the 4 and 7 chlorinated positions of the quinazoline ring (Scheme 2). We started by using 4 equiv. of 4-methoxyphenylboronic acid, 4 equiv. of Na 2 CO 3 and 2.5 mol % of Pd(PPh 3 ) 4 . As suggested by Connolly and co-workers [34], a DME/ethanol (9:1, v/v) mixture was used as solvent and the reaction was heated with microwave irradiation. Under such conditions, only the double-coupled compound 7a was obtained, in 70% yield, as presented in Table 1 (Entry 1), showing that both positions were reactive as regards of the Suzuki-Miyaura reaction.
To minimize double coupling and substitute at the 4-position selectively, we decreased the amount of arylboronic acid. Using 1.5 equiv. of 4-methoxyphenylboronic acid (Entry 2), some selectivity appeared, the reaction mixture containing both the monosubstituted product 6a (45% yield) and the disubstituted product 7a (15% yield). However, a complete selectivity was observed with 1.2 equiv. of 4-methoxyphenylboronic acid. The monosubstituted product 6a was then obtained in good yield (68%, Entry 3). This result indicates the possibility of achieving a selective coupling reaction at the C4 position, while preventing the chlorinated C7 position from reacting. The monocoupling at the 4position was checked by NOESY spectrum, where a strong correlation between H-5 (8.65 ppm) and H-2' (7.77 ppm) was observed. Table 1. Regioselective Suzuki-Miyaura coupling reaction.

Entry
Arylboronic acid Aryl-Equiv. of Boronic acid Yield % (6/7) Starting from this initial encouraging result, the influence of both electron-withdrawing and electron-donating substituents on arylboronic acids was investigated next. The reactions with 1.5 equiv. of 4-chlorophenylboronic or 3-trifluoromethylphenylboronic acid provided the monosubstituted products 6b or 6c in 63 and 48% yields, respectively (Entries 6 and 7). The reaction of 5 with 3-nitrophenylboronic acid offered lower reactivity in comparison with the reaction of 5 with 4-methoxyphenylboronic acid but higher regioselectivity, especially when 2 equiv. of arylboronic acid were used (Entry 10), leading to the monosubstituted product 6e in 55% yield. A possible explanation for the lower reactivity and good regioselectivity observed when using 3-nitro or 3-trifluorophenylboronic acid and 5-methylthiophen-2-ylboronic acid could result from the chelation of the Lewis basic heteroatoms to the palladium intermediate. Such chelation could be retarding the rate of the reductive elimination step [35]. By using the preceding best conditions for the double coupling reaction, defined for the preparation of compounds 7a and 7b, three more symmetric diarylquinazolines 7f-h were synthesized in good yields ( Table 2). Reaction conditions: arylboronic acid (4 equiv.), Pd(PPh 3 ) 4 (2.5 mol %), Na 2 CO 3 (4 equiv.), DME/ethanol (9:1), MW 300 W, 80 °C, 3 h In order to achieve the second coupling reaction at the C7 position of monosubstituted product 6a, and obtain dissymmetric diarylquinazolines, we started by using 2 equiv. of arylboronic acid, 3 equiv. of Na 2 CO 3 , 2.5 mol % of Pd(PPh 3 ) 4 and a refluxing mixture of DME/ethanol (9:1, v/v). After 3 h, under microwave irradiation, starting material 6a and the diarylsubstituted product 8 were obtained in a 1:1 ratio (27% yield), indicating the lack of reactivity of the C7 quinazoline position under such reaction conditions, probably due to the insufficient solubility of 6a in the reaction mixture.
We then proceeded to modify the operating procedure. The DME/ethanol solvent mixture was changed for a DMF/ethanol (9:1) mixture which was refluxed under microwave irradiation (Scheme 3). After 3 h, all the starting material was consumed. A series of dissymmetric diarylquinazolines 8-16 was thus synthesized in good yields via this optimized coupling reaction between 6a or 6b and various arylboronic acids, as indicated in Table 3.

General
Melting points were determined on a Büchi B-540 apparatus and are uncorrected. Elemental analyses were performed by the Microanalyses Center of the University of Aix-Marseille 3, France. Both 1 H-and 13 C-NMR spectra were determined on a Bruker ARX 200 spectrometer. The 1 H chemical shifts are reported as ppm downfield from tetramethylsilane (Me 4 Si), and the 13 C chemical shifts were referenced to the solvent peak: CDCl 3 (76.9 ppm) or DMSO-d 6 (39.5 ppm). Solvents were dried by conventional methods. The following adsorbent was used for column chromatography: silica gel 60 (Merck, particle size 0.063-0.200 mm, 70-230 mesh ASTM). TLC was performed on 5 cm × 10 cm aluminium plates coated with silica gel 60F-254 (Merck) in an appropriate solvent.

Microwave instrumentation
Multimode reactor: ETHOS Synth Lab station and MicroSYNTH Lab terminal 1024 (Ethos start, Milestone Inc.). The multimode microwave has a twin magnetron (2 × 800 W, 2.45 GHz) with a maximum delivered power of 1,000 W in 10 W increments (pulsed irradiation). Built-in magnetic stirring (Teflon-coated stirring bar) was used in all operations. During experiments, time, temperature and power were measured with the "easy WAVE" software package. The temperature was measured throughout the reaction and evaluated by an infrared detector or a optical fiber (ATC-FO 300). (2) [31] were prepared as previously described.

Conclusions
We have reported herein an efficient and regioselective access to symmetric and dissymmetric 4,7diarylquinazolines by using the Suzuki-Miyaura reaction on the 4,7-dichloroquinazoline derivative 5, under microwave irradiation. The regioselectivity was controlled by modifying both the amount of arylboronic acid used and the nature of the reaction medium. This method opens the way to a general synthesis of bis-functionalized quinazolines, skeletons of great interest for designing biologically active compounds.