Microwave-assisted synthesis of macrocycles via intramolecular and/or bimolecular Ullmann coupling

Abstract

Microwave-assisted synthesis of macrocyclic diaryl ethers via intramolecular and/or bimolecular Ullmann coupling is described. Using the optimized conditions, a panel of macrocycles, with different substitution patterns, ring sizes, and linkers, has been successfully synthesized using microwave irradiation. To the best of our knowledge, this work represents the first examples of the microwave-assisted synthesis of macrocyclic diaryl ethers via intramolecular and/or bimolecular Ullmann coupling.

Macrocyclic diaryl ether motifs are commonly found in naturally occurring molecules (Figure 1) and have been reported to mediate a broad range of biological activities.¹ The Ullmann coupling reaction of phenols and aryl halides has been widely used for the synthesis of diaryl ethers since its discovery; however, the scope of Ullmann coupling has been limited by harsh reaction conditions (e.g., high temperature and long reaction time) and low reaction yields.² Therefore, much effort has been devoted to the modifications of this classical coupling reaction.³ For example, the generality has been improved by the introduction of palladium catalysts⁴ and with the assistance of novel ligands such as N,N-dimethylglycine⁵ and biarylphosphine.⁶ So far, however, most improvements have been achieved with the intermolecular Ullmann coupling of small molecular aryl halides with phenols.

Figure 1.

Representative examples of diaryl ether-based natural products.

The application of microwave (MW) irradiation in promoting organic reactions has been demonstrated successfully in recent years.⁷ It has been shown in many studies that MW irradiation can accelerate reaction rates and improve chemical yields. MW heating has also been explored for intermolecular Ullmann reactions⁸ and for the synthesis of diversified macrocycles based on ring-closing metathesis (RCM),⁹ Suzuki-Miyaura crosscoupling, ¹⁰ and solution and solid-phase synthesis of cyclic peptides and peptidomimetics.¹¹ However, no reports have been found in the literature concerning MW-assisted intramolecular Ullmann macrocyclization. During the course of our continued effort to synthesize diaryl ether macrocycles, we reported recently the first total synthesis of macrocyclic engelhardione using a sealed pressure tube which led ultimately to the structural revision of its published structure.¹² To further improve the efficiency and to develop a modular synthesis of diaryl etherbased macrocycles, MW methodology has been applied to the intramolecular Ullmann reaction. Herein the synthesis of a panel of macrocycles with different substitution patterns, ring sizes, and linkers via the MW-assisted Ullmann cross-coupling is reported (Scheme 1).

Scheme 1.

MW-assisted synthesis of macrocycles via intramolecular and/or bimolecular Ullmann reaction.

To screen the reaction conditions, the macrocyclization of 1,7-diarylheptan-3-one 1a to 2a (Table 1) was selected as a model reaction. The reaction was conducted under an array of different conditions, including conventional heating, sealed pressure tube, and MW irradiation; the results are shown in Table 1. As noted previously,¹² the reaction proceeded slowly under reflux at 150 °C for 20 h to give the macrocyclic product 2a in 33% yield (entry 1). An improved yield and a significant decrease in reaction time were observed when the reaction was conducted in a sealed pressure tube. The reaction was completed after 4.5 h at 175 °C and 1 h at 200 °C to provide 2a in 52% and 44% yields, respectively (entries 2 and 3). Using the optimized reaction conditions in a sealed tube as a starting point, further improvement was achieved when the reaction was performed using MW irradiation. When the macrocyclization step was initially performed at 175 °C using MW heating, approximately 5% of 2a was produced after 10 min based on HPLC monitoring of the reaction mixture with the remaining as the unreacted 1a. After the temperature was increased to 200 °C, similar to the reaction in a sealed tube, the reaction was completed in 1 h with a much higher yield (73% vs 44%, entries 6 and 3). Further improved results were obtained when the temperature was raised to 220 °C, the reaction finished after 35 min in excellent yield (85%, entry 7). In contrast, the cyclic reaction was completed in 15 min at 230 °C, affording 2a in a comparable yield (76%, entry 8).

Table 1.

Optimization of intramolecular macrocyclic Ullmann coupling^a

Entry	Condition	Temp. (°C)	Time	Yield (%)b
1c	Reflux	150	20 h	33
2c	Sealed tube	175	4.5 h	52
3c	Sealed tube	200	1 h	44
4d	Sealed tube	>200	30 h	52
5	Microwave	175	10 min	5e
6	Microwave	200	1 h	73
7	Microwave	220	35 min	85
8	Microwave	230	15 min	76

^aAll experiments except entry 4 were performed using 0.08 mmol of 1a, 0.2 mmol of CuO, 0.08 mmol of K2CO3, and 4 mL of pyridine.

^bIsolated yield based on flash column chromatography on silica gel.

^cref 12.

^dref 13.

^eHPLC yield of the reaction mixture.

With the optimized MW conditions in hand, a panel of different substrates 1b-r¹⁴ containing diverse phenol and aryl bromide moieties was employed to evaluate the scope and generality of this macrocyclic Ullmann condensation reaction; the results are shown in Table 2. Initially, a set of substrates 1b-f with a seven-carbon linker was investigated (entries 2-6). Consistent with the meta-meta substituted 2a with a 14-membered ring (entry 1), the O-MOM protected 2b was obtained in 85% yield using MW irradiation for 40 min (entry 2). In contrast, a lower yield (63%) of 2b was isolated using a sealed tube at 175 °C for 4 h. As expected, intramolecular 15-membered macrocycles 2c-d were obtained for the para-meta and meta-para substituted substrates 1c-d in 44% and 69% yields, respectively (entries 3-4). It is worth noting that these yields under MW irradiation have been improved than reported yields (12% and 50%, respectively) using sealed tubes.¹³ A similar result was anticipated for the meta-ortho substituted substrate 1e; surprisingly, the dimeric macrocycle 3e was isolated as a major product¹⁵ (21% yield) together with the intramolecular cyclic product 2e in 10% yield (entry 5).

Table 2.

MW-assisted synthesis of macrocycles via intramolecular and/or bimolecular Ullmann chemistry^a

Entry	Substrate	Time	Product	Yield (%)b
1		35 min		85
2		40 min		85 (63c)
3		35 min		44 (12d)
4		40 min		69 (50d)
5		1.5 h		21e
6		1 h		11e
7		40 min		85 (28f)
8		50 min		83
9		40 min		73
10		2.5 h		28 (7g)
11		5 h		18
12		2.5 h		18
13		40 min		48
14		40 min		56
15		1.5 h		44
16		6 h		16
17		2 h		0h
18		1 h		25

^aAll experiments were performed using 0.08 mmol of substrate 1, 0.2 mmol of CuO, 0.08 mmol of K₂CO₃, and 4 mL of pyridine. Reaction mixtures were heated to 230 °C (220 °C for entries 1-3 and 18) using Biotage Initiator 8 Exp Microwave System and monitored by analytical HPLC.

^bIsolated yield based on flash column chromatography on silica gel.

^cIsolated yield using a sealed tube at 175 °C for 4 h.

^dReported yields using sealed tubes in the same reaction system, see ref 13.

^eIntramolecular Ullmann coupling products 2e and 2f were also obtained in 10% and 9% yields, respectively.

^fReaction was performed in a higher concentration (using 0.4 mmol of 1g, 1 mmol of CuO, 0.4 mmol of K₂CO₃, and 4 mL of pyridine) and completed in 15 min.

^gReaction was performed under conventional reflux and was completed after 46 h.

^hReaction mixture was heated at 220 °C for 1 h, and then at 230 °C for another 1 h.

To further investigate the effect of the linker flexibility on the outcome of macrocylization, the substrate 1f with a more rigid ketone-conjugated linker was explored, and, as expected, a dramatic decrease of reactivity and reaction yield were noted compared to its close analogue 1a; again, both the dimeric macrocycle 3f and the intramolecular coupling product 2f were afforded in 11% and 9% yields, respectively (entry 6).

Next, the macrocyclization reaction for a second set of substrates with a shorter five-carbon linker was examined and, again, in the case of the meta-meta substituted substrate 1g, the intramolecular Ullmann coupling proceeded smoothly to give the 12-membered macrocycle 2g in 40 min in 85% yield (entry 7). Comparable and consistent results were obtained for the meta-meta substituted 1h-i with only one substituted MeO group affording the identical macrocycles 2h-i in good yields (entries 8-9). However, interesting results were obtained for the other fivecarbon linked substrates 1j-l with the para-meta, meta-para, and meta-ortho substitution patterns (entries 10-12). In all cases, the substrates 1j-l were much less reactive than 1g-i under the same MW conditions and the bimolecular macrocyclization products 3j-l were obtained in 18-28% yields after prolonged reaction times (2.5-5 h);¹⁵ no intramolecular Ullmann coupling products were observed (entries 10-12). The formation of the dimeric cyclic products is presumably due to further reduced conformational flexibility of the substrates and unfavorable ring strains needed to perform the intramolecular coupling. Instead, the alternative intermolecular Ullmann coupling occurred first, followed by the bimolecular macrocyclization. In comparison, only 7% of 3j was isolated for the reaction performed under conventional reflux for 46 h (entry 10). Moreover, to study the potential effect of the carbonyl group in the linker on macrocyclization, reactions of the corresponding reduced variants 1m-o with the racemic alcohol functionalities were carried out, and both reactions of 1m-n afforded the expected intramolecular cyclic products 2m-n in moderate and lower yields by comparing entries 13 and 14 with corresponding entries 7 and 9. These data are consistent with the previous reports indicating that the ketone functionality may play a role in controling the substrate’s conformation and facilitating subsequent polyketide macrocyclization.¹⁶ In the case of 1o, it should be noted that the introduction of the secondary alcohol functionality appeared to facilitate the intermolecular coupling and subsequent bimolecular macrocyclization and the reaction was completed in a much shorter time (1.5 h vs 5 h), giving the bimolecular macrocycle 3o in a higher yield (44% vs 18%) compared to 1k (entries 15 and 11).

The cyclizations of the substrates 1p-r with an even shorter three-carbon linker were then studied. Different from its close analogues 1a and 1h with a longer seven- and five-carbon linker, the intermolecular cyclization product 3p was obtained in low yield (16%) for the reaction of the meta-meta substituted substrate 1p (entry 16), whereas the intramolecular macrocycle 2r was afforded in 25% yield for the reaction of the ortho-ortho substituted substrate 1r (entry 18); however, under the same MW conditions, no product was isolated from the reaction of 1q with OH and Br groups in ortho and meta positions, respectively (entry 17). The observed decrease in reactivity is presumably due to further restricted conformational flexibility originating from the conjugated ketone and unfavorable ring strains. Finally, to test the effect of concentration on the outcome of macrocyclization, the reaction of 1g with a five-fold higher concentration (0.4 M) was tried. It was found that the intramolecular coupling product 2g was obtained as a sole product despite a much lower yield (28%, entry 7),¹⁷ and no intermolecular cyclization product was observed.

The macrocycles 2 and 3 were characterized by ¹H, ¹³C and 2D NMR spectroscopy, and high-resolution mass spectrometry (HRMS). The structures of the intramolecular product 2a and the bimolecular macrocycle 3j were confirmed by X-ray crystallography, their ORTEP drawings are shown in Figures 2 and 3, respectively^.18,19

Figure 2.

ORTEP view of the molecular structure of 2a at 100 K; 30% probability ellipsoids are shown.¹⁸

Figure 3.

ORTEP views using 30% probability ellipsoids at 90 K of the two crystallographically independent molecules of 3j in the unit cell; each has inversion centers.¹⁹

In summary, a modular MW-assisted synthesis has been developed for the intramolecular and/or bimolecular Ullmann condensation of macrocyclic diaryl ethers. Under the optimized MW irradiation conditions, improved yields and shorter reaction times of intramolecular Ullmann coupling were noted compared with conventional heating and sealed tubes. These data show that the outcome of intramolecular and/or bimolecular macrocyclization depends on the linker length and substitution patterns of the substrates. This study further demonstrates that the 14- and 12-membered intramolecular macrocyclization proceeded more favorably for the meta-meta substituted substrates. To the best of our knowledge, this work represents the first examples of the MW-assisted synthesis of macrocycles via the Ullmann coupling chemistry. Further biological testing is warranted to screen these macrocyclic novel chemical entities as potential pharmacological tools and/or useful molecular probes.