Organocatalytic Synthesis of Methylene-Bridged N-Heterobiaryls

Abstract

A one-step synthesis of 1,1′- and 2,2′-methylene-bridged N-heterobiaryls directly from the corresponding N-heterocycles in a reaction with methylmagnesium chloride in the presence of catalytic amounts of N,N,N′N′-tetramethylethylenediamine (TMEDA) under thermal and microwave conditions is reported. The split-and-merge methylenation of 2,2′-N-heterobiaryls and the direct ortho-alkylation of quinoline and isoquinoline with Grignard reagents have also been developed. Mechanistic studies identified several intermediates and provided insights into the formation and roles of magnesium hydride species in the process.

ortho-Methylene-bridged N-heterobiaryls 1 are an important class of nitrogenous heterocycles with applications in drug discovery,¹ catalyst and ligand design,² and materials science.³

ortho-Methylene-bridged N-heterobiaryls 1 were previously synthesized in several steps,^2b or at very high temperatures.⁴ We hypothesized that 1 could be accessed directly from the corresponding N-heterocycles 2 by a reaction with methylmagnesium halide (Scheme 1). In this case, addition of the Grignard reagent to 2 would produce intermediate 3 that could undergo elimination of HMgX. Disproportionation of MgHX produces magnesium hydride and magnesium halide, as previously observed in Singaram pinacolboronate ester synthesis.^5,6 Deprotonation of 2-methylazine 4 would produce anionic species 5 that can add to 2 to give chelate 6. Subsequent elimination of HMgX and deprotonation of the methylene group would furnish intermediate 7 that would produce ortho-methylene-bridged N-heterobiaryl 1 upon aqueous work-up.

Scheme 1.

Direct Synthesis of ortho-Methylene-Bridged N-Heterobiaryls from N-Heterocycles

We report herein that the scalable synthesis of ortho-methylene-bridged N-heterobiaryls 1 can be accomplished directly from the corresponding N-heterocycles in the presence of catalytic amounts of TMEDA (N,N,N′,N′-tetramethylethylenediamine).

Initial experiments showed that di(isoquinolin-1-yl)methane (9) is produced in 7% yield on treatment of isoquinoline (8) with MeMgCl in hexane at 120 °C (Table 1, entry 1). Addition of TMEDA led to a significant improvement of the yield (entries 2 and 3).

Table 1.

Reaction Conditions for the Synthesis of ortho-Methylene-Bridged N-Heterobiaryls^a

Entry	Amine (equiv)	X	Solvent	Time (h)	Temp (°C)	Yield (%)
1	–	Cl	hexane	2	120	7
2	TMEDA (1.3)	Cl	toluene	2	120	93
3	TMEDA (1.3)	Cl	hexane	2	120	78
4	DABCO (1.3)	Cl	hexane	2	120	7
5	PMDTA (1.3)	Cl	hexane	2	120	15
6	DMEDA (1.3)	Cl	hexane	2	120	0
7	TMEDA (0.2)	Cl	toluene	14	140	95
8b	TMEDA (0.1)	Br	toluene	14	140	97
9b	TMEDA (0.1)	I	toluene	14	140	65

^aIsoquinoline (2 mmol), MeMgX (3 equiv), solvent (2 mL). 1,4-Dimethoxybenzene was used as an internal standard added prior to work-up.

^b1 mL of toluene was used. PMDTA = N,N,N′,N″,N″-pentamethyldiethylenetriamine. DMEDA = N,N′-dimethylethylenediamine.

The optimal temperature range was 120–140 °C, and hexane and toluene were both suitable solvents. Other amines were inferior to TMEDA (entries 4–6), and the starting material remained largely unconsumed. Further experiments showed that the reaction can be carried out efficiently with catalytic amounts of TMEDA (entries 7 and 8). Both methylmagnesium chloride and bromide worked well, while a lower yield was observed for MeMgI (entries 7–9).

The reaction tolerates a number of functional groups (Figure 1). Quinolines and isoquinolines with substituents in 3, 4, 5, 6 and 7 positions have produced corresponding ortho-methylene-bridged biquino-lines and biisoquinolines (8, 10–21) in good to excellent yields. The reaction was also successfully carried out under the microwave irradiation. Further, products 9 and 10 were synthesized on a preparative scale (6.3 g and 1.9 g, respectively).

Figure 1.

Organocatalytic Synthesis of ortho-Methylene-Bridged N-Heterobiaryls

Quinolines reacted regioselectively at C2 position, while isoquinolines produced the 1,1′-methylene-bridged products. C2-methylene-bridged bipyridines were not observed, when pyridines were subjected to the standard reaction conditions.

4,4′-Methylene-bridged biquinoline 22 was readily obtained by a reaction of 4-chloroquinoline 23 with MeMgCl in the presence of TMEDA (Scheme 2). 4-Hydroxyquinolne (24) also produced 4,4′-methylene-bridged biquinoline 22, indicating that 4-hydroxy group can be readily displaced by a Grignard reagent under these conditions.

Scheme 2.

Synthesis of 4,4′-Methylene-Bridged N-Heterobiaryls

Interestingly, 1,1′-biisoquinoline and 2,2′-biquinoline underwent a C–C bond cleavage with subsequent formation of the methylene-bridged products 9 and 10 in excellent yields, indicating that an unusual and facile C-nucleophile/C-nucleofuge displacement takes place under the reaction conditions (Scheme 3). Since substituted 1,1′-biisoquinolines and 2,2′-biquinolines can be prepared in a scalable manner from the corresponding N-oxides,⁷ this route offers additional flexibility in the synthesis of ortho-methylene-bridged N-heterobiaryls.

Scheme 3.

Split and Merge Synthesis of ortho-Methylene-Bridged N-Heterobiaryls from 2,2′-Biquinoline and 1,1′-Biisoquinoline

We have further investigated the reactions of quinoline and isoquinoline with other alkylmagnesium halides (Figure 2). The reactions did not produce ortho-methylene-bridged N-heterobiaryls, but instead afforded the corresponding 2-alkylquinolines (25 and 26) and 1-isopropylisoquinoline (27). These results are in line with the observation of TMEDA-catalyzed arylation of azines with arylmagnesium bromides reported by Da.⁸ No functionalization of the distal positions⁹ was observed for quinolines and isoquinoline. This direct alkylation reaction is complimentary to the deoxygenative ortho-alkylation of heterocyclic N-oxides.¹⁰

Figure 2.

Synthesis of 2-Alkylquinolines and 2-Alkylisoquinolines

Several experiments were carried out to clarify the mechanism of the reaction. First, monitoring of the reaction of isoquinoline with methylmagnesium chloride in the presence of TMEDA in C₆D₆ at 50 °C by means of ¹H NMR spectroscopy identified several intermediates along the reaction pathway (Scheme 4). Formation of the Grignard addition product 28, as well as 1-methylisoquinoline (29) that arises from the loss of HMgX was observed. Further, magnesiated di(isoquinolin-1-yl)methane intermediate 30 was also detected. Interestingly, formation of 1,2-dihydroisoquinoline intermediate 31 was also observed. Addition of magnesium hydride species to pyridines is a reversible process.¹¹ Indeed, when 1-d₁-isoquinoline was heated with 25 mol% MgH₂¹² in the presence of TMEDA (1 equiv) in d₈-toluene for 2 h at 110 °C, 20% H/D exchange (40% after 21 h) took place in C1 position of isoquinoline, indicating that magnesium hydride addition to isoquinoline is reversible under the reaction conditions. Intermediate 31 may serve as a pool of soluble magnesium hydride species in solution. It is also possible that a hydride transfer takes place directly to isoquinoline from 1,2-dihydroisoquinoline intermediates 28 and 32,¹³ facilitating their aromatization. In order to further investigate the formation and roles of magnesium hydride species in the methylenation process, the amount of hydrogen produced in the reaction of quinoline with methylmagnesium chloride in the presence of TMEDA in hexane at 120 °C was determined by means of gas chromatography.

Scheme 4.

Intermediates in the Reaction of Methylmagnesium Chloride with Isoquinoline

Interestingly, hydrogen was formed even before quenching the reaction mixture with methanol (0.45 mmol H₂ per 1 mmol of quinoline), indicating that magnesium hydride participates in the deprotonation of intermediates 9 and 29 en route to magnesiated species 30 and 33. Addition of methanol after the reaction led to generation of 0.7 mmol of hydrogen per 1 mmol of quinoline, in agreement with the observed 73% conversion of quinoline.

ortho-Methylene-bridged N-heterobiaryls 1 can be readily oxidized to the corresponding ketones that are useful bidentate chelators.¹⁴ For example, diquinolinylmethanes 16 and 17 were oxidized by air in the presence of potassium tert-butoxide to give ketones 34 and 35 in 95% and 78% yields, respectively (Scheme 5).

Scheme 5.

Oxidation of the methylene group in diquinolinylmethanes 16 and 17

In conclusion, a simple, one-step synthesis of ortho-methylene-bridged biquinolines and biisoquinolines has been developed. The reaction is catalyzed by an organic base (TMEDA). Furthermore, the efficient split and merge methylenation of biquinolines and biisoquinolines by methylmagnesium chloride in the presence of TMEDA as a catalyst has also been described. ortho-Alkylation of quinoline and isoquinoline has been observed with other alkylmagnesium reagents. Mechanistic studies point to a reversible elimination of magnesium hydride species en route to ortho-methylene-bridged N-heterobiaryls. The methylene bridge in the products of methylenation can be readily oxidized by air in the presence of potassium tert-butoxide.