Ligand-free Cu-catalyzed O-arylation of aliphatic diols

Abstract

Coupling reaction between aryl iodides and aliphatic diols was realized with a ligand-free copper catalyst under mild conditions. This method was successfully applied in the process of scale-up synthesis of medicinal candidate product EMB-3.

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Introduction

Since Ma et al. reported the first effective ligand amino acid (L1, Fig. 1) for copper catalysis in the synthesis of enantiopure N-aryl-α-amino acids from R-amino acids with aryl halides in 1998,^1,2 Brønsted bases,^3,4 phenanthroline (L2, Fig. 1),⁵ 1,2-diamino-cyclohexane (L3, Fig. 1)^6–8 and several other representative ligands (L4–L7, Fig. 1) have been reported as effective ligands in the CuI-catalyzed aryl amination.⁹ Based on these novel ligands, many chemoselective methods, such as C_sp²- or C_sp³-N-arylation,¹⁰ C_sp²-S-arylation¹¹ and C_sp²-O-arylation¹² have been studied. However, only a few reported copper catalyst systems could facilitate the coupling between aryl halides and aliphatic alcohols¹³ because of the weak nucleophilic ability of aliphatic alcohols. For example, researchers, including Buchwald et al., reported a highly efficient phenanthroline ligand (L2, R¹, R², R³, R⁴ = Me, Fig. 1) in the amination of aryl iodides under mild conditions.^14–16

Fig. 1 Representative ligands for the Ullmann reaction.

Avoiding the use of different complex and expensive ligands, “ligand-free” copper catalyst systems have been reported recently in the O-arylation of aliphatic alcohols (17–59% yields, Scheme 1a).¹⁷ However, the reaction substrate was very narrow and high temperatures were required. In addition, the yield of desired ethers was very low and was just determined exclusively using ¹H-NMR spectroscopy. Maiti reported an efficient ligand-free Cu-catalyzed O-arylation of aliphatic alcohols 4 and aryl iodide 2 to produce alkyl aryl ether 5 in the presence of 2.3 equivalents of NaO^t-Bu (Scheme 1b).¹⁸ Although this “ligand-free” methodology was further tested in the one-step synthesis of 2-(2-(4-fluorophenoxy)ethyl)-phenol (CRE 10904: 2-OH, n = 1, R = 4-F, Scheme 1b), it could not be transposed on industrial scale because of its relative low yield of 50%. Very recently, Chae reported a Cu-catalyzed O-arylation of aliphatic alcohols with aryl bromide as substrate and CuCl₂ as catalyst (83–99% yields). However, this protocol was effective for the aryl bromide and the required temperature (at 130 °C) was high.¹⁹ Therefore, ligand-free Cu-catalyzed O-arylation of aliphatic alcohols remains a challenge.

Scheme 1 Ligand-free Cu-catalyzed O-arylation of aliphatic alcohols.

Our research group has engaged in metal-catalyzed coupling transformation including C–C coupling reactions²⁰ and C–S coupling reactions.²¹ For the purpose of extending to C–O coupling reactions, the efficiency of ligand-free copper-catalyzed C_sp³-O-alkyl chain was investigated. Herein, we disclose a simple and practical ligand-free procedure for the copper-catalyzed arylation of different primary and secondary aliphatic diols (Scheme 1c).

Results and discussion

4-Fluoro-iodobenzene 2a and 1, 4-butanediol 6a were selected as model substrates in the experiment under various conditions (Table 1). After 2a was treated with 6a (3.0 equiv.) in the presence of CuI (5 mol%) and NaO^t−Bu (3.0 equiv.) in N,N-dimethylformamide at 70 °C for 18 h, product 7a was isolated with a yield of 76% (Table 1, entry 1). Upon using CuBr as the catalyst, product 7a was obtained in lower yield (Table 1, entry 2). As shown in Table 1 (entries 1, 3–5), the amount of CuI had limited influence on the yield. Entries 6–9 in Table 1 show that NaO^t-Bu was essential for the coupling reaction because 7a was not obtained with K₂CO₃, K₃PO₄, Cs₂CO₃ or Et₃N. Entries 10–14 in Table 1 also show that solvent effects were significant and product 7a could not be produced in THF, DMSO, 1,4-dioxane, MeCN or toluene instead of DMF. When reaction temperature was increased to 80 °C from 70 °C, the yield of 7a was unchanged, but a further increase over 80 °C evidently decreased the yields (Table 1, entries 15–18). When the dosage of diol was increased to 5.0 equiv. or decreased to 1.5 equiv., 7a was isolated in a yield of 78% and 55%, respectively (Table 1, entries 19 and 20). As shown in Table 1, 7a wasn't obtained when CuI wasn't used (entry 22) or when a small amount of water was added (entry 23) or when 1,4-butanediol was replaced by 1-butanol (Table 1, entry 21), suggesting that 1,4-butanediol was the starting material and also the ligand. Therefore, reaction conditions were determined to include CuI (10 mol%) as the catalyst and NaO^t-Bu (3.0 equiv.) as the base in DMF at 80 °C with a 2a/6a molar ratio of 1 : 3 for 18 h (Table 1, entry 15).

Table 1 Optimization of reaction conditions^a

Entry	Copper	Base	Solvent	Temp. (°C)	Yields^b (%)
a Reaction conditions: 2a (0.5 mmol), 6a (1.5 mmol, 3.0 equiv.), copper catalyst (0.05–0.2 mmol), base (1.5 mmol, 3.0 equiv.), solvent (2 mL), 18 h.b Isolated yields calculated based on 2a.c 5.0 equiv. 1,4-butanediol was used.d 1.5 equiv. butanediol was used.e 1,4-Butanediol was replaced by 1-butanol.f 4-(4-Iodophenoxy)butan-1-ol 7t instead of 7a was obtained and the structure was confirmed by ^19F-NMR, ^1H-NMR and ^13C-NMR.g 0.5 mL H2O was added to the reaction system.
1	CuI (5 mol%)	NaO^t-Bu	DMF	70	76
2	CuBr (5 mol%)	NaO^t-Bu	DMF	70	58
3	CuI (10 mol%)	NaO^t-Bu	DMF	70	77
4	CuI (15 mol%)	NaO^t-Bu	DMF	70	65
5	CuI (20 mol%)	NaO^t-Bu	DMF	70	76
6	CuI (10 mol%)	K2CO3	DMF	70	0
7	CuI (10 mol%)	K3PO4	DMF	70	0
8	CuI (10 mol%)	Cs2CO3	DMF	70	0
9	CuI (10 mol%)	Et3N	DMF	70	0
10	CuI (10 mol%)	NaO^t-Bu	THF	70	0
11	CuI (10 mol%)	NaO^t-Bu	DMSO	70	0^f
12	CuI (10 mol%)	NaO^t-Bu	1,4-dioxane	70	0
13	CuI (10 mol%)	NaO^t-Bu	MeCN	70	0
14	CuI (10 mol%)	NaO^t-Bu	Toluene	70	0
15	CuI (10 mol%)	NaO^t-Bu	DMF	80	78
16	CuI (10 mol%)	NaO^t-Bu	DMF	90	69
17	CuI (10 mol%)	NaO^t-Bu	DMF	100	58
18	CuI (10 mol%)	NaO^t-Bu	DMF	110	67
19	CuI (10 mol%)	NaO^t-Bu	DMF	80	78^c
20	CuI (10 mol%)	NaO^t-Bu	DMF	80	55^d
21	CuI (10 mol%)	NaO^t-Bu	DMF	80	0^e
22	CuI (0 mol%)	NaO^t-Bu	DMF	80	0^f
23	CuI (10 mol%)	NaO^t-Bu	DMF	80	0^g

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To further test this reaction, 6a was reacted with various aryl iodides under the optimized reaction conditions. As shown in Table 2, with some electron-withdrawing groups, such as Cl, Br and phenyl, the desired products were obtained in relatively moderate yields (Table 2, entries 4, 5 and 9). However, with other electron-withdrawing groups, such as cyano, trifluoromethyl and benzoyl, the corresponding products were obtained only in very low yield probably due to their strong electron-withdrawing effects (Table 2, entries 6–8). Iodobenzenes bearing one or two electron-donating groups on the phenyl ring, such as 2j, 2k, 2l, 2m, 2n, 2r and 2s reacted with 6a to form the coupled products in low to moderate yields (Table 2, entries 10–14, 18 and 19). In addition to para-substituted iodobenzene 2a and 2l, meta-substituted substrate 2b, ortho-substituted substrate 2c and 2m were also successfully applied to this transformation with relatively low yield (Table 2, entries 2, 3 and 13). Furthermore, iodides with phenyl ring, pyridine ring or thiophene ring gave the desired coupled products (7o: 77%, 7p: 74% and 7q: 53%) without much yield loss (Table 2, entries 15–17). When reaction temperature was decreased to 70 °C from 80 °C, product 7l and 7o were obtained in slightly lower yield (73 and 74% respectively), proving 80 °C was more efficient than 70 °C (Table 2, entries 12 and 15).

Table 2 Synthesis of alkyl aryl ethers 7 from aryl iodides 2 and 1,4-butane-diol 6a^a

Entry	Ar (Het)	7	Yields^b (%)
a Reaction conditions: 2 (0.5 mmol), 6a (1.5 mmol, 3.0 equiv.), CuI (0.05 mmol, 10 mol%), NaO^t-Bu (1.5 mmol, 3.0 equiv.), DMF (2 mL), 80 °C, 18 h.b Isolated yields calculated based on 2.c At 70 °C.d CuI was not added.
1	2a 4-F-C6H4	7a	78
2	2b 3-F-C6H4	7b	68
3	2c 2-F-C6H4	7c	58
4	2d 4-Br-C6H4	7d	82
5	2e 4-Cl-C6H4	7e	80
6	2f 4-CN-C6H4	7f	30
7	2g 4-CF3-C6H4	7g	44
8	2h 4-Bz-C6H4	7h	38
9	2i 4-Ph-C6H4	7i	64
10	2j 4-NHAc-C6H4	7j	35
11	2k 4-OMe-C6H4	7k	63
12	2l 4-Me-C6H4	7l	78 (73^c)
13	2m 2-Me-C6H4	7m	58
14	2n 4-OCF3-C6H4	7n	70
15	2o C6H5	7o	77 (74^c)
16	2p 2-Pyridinyl	7p	74 (Trace^d)
17	2q 3-Thiophenyl	7q	53
18	2r 3,5-Dimethyl-C6H3	7r	72
19	2s 2,4-Dimethoxyl-C6H3	7s	49

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When various diols, including aliphatic diols 6b–e and methyl or benzyl substituted diethanol amine 6f–g, were used, the desired products were obtained in 45–86% yields (Table 3, entries 1–9). Compared with 6a, aliphatic diols 6b–e gave the corresponding products 8a–d in lower yields (Table 3, entries 1–4), which indicated that the chain length of aliphatic diols might affect the reaction efficiency. Comparing between N-methyl diethanol amine 6f and N-benzyl diethanol amine 6g, which had comparable reactivities as 6a, 6g exhibited higher reactivity with better yields (Table 3, entries, 5 and 6). Aryl iodides 2a, 2o and 2r reacted with 6f or 6g to afford the desired products in 52–77% yields (Table 3, entries 7–9).

Table 3 Synthesis of alkyl aryl ethers 8 from aryl iodides 2 and diols 6^a

Entry	2	6	8	Yield^b [%]
a Reaction conditions: 2 (0.5 mmol), 6 (1.5 mmol, 3.0 equiv.), CuI (0.05 mmol, 10 mol%), NaO^t-Bu (1.5 mmol, 3.0 equiv.), DMF (2 mL), 80 °C, 18 h.b Isolated yields calculated based on 2.
1	2l	6b		59
2	2l	6c		60
3	2l	6d		61
4	2l	6e		45
5	2l	6f		76
6	2l	6g		86
7	2o	6f		52
8	2a	6g		77
9	2r	6g		65

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To further examine the scope of diols, 2,5-hexanediol 9 was tested under the optimized conditions. As shown in Table 4, iodobenzene derivatives containing electron-donating or electron-withdrawing groups on the aryl moiety reacted with 2,5-hexanediol to produce the corresponding products in 36–78% yields, which indicated that the steric hindrance on diols had limited impact on the reaction.

Table 4 Synthesis of alkyl aryl ethers 10 from aryl iodides 2 and 2,5-hexanediol 9^a

Entry	Ar (Het)	10	Yield^c [%]
a Reaction conditions: 2 (0.5 mmol), 9 (1.5 mmol, 3.0 equiv.), CuI (0.05 mmol, 10 mol%), NaO^t-Bu (1.5 mmol, 3.0 equiv.), DMF (2 mL), 80 °C, 18 h.b Mixture of isomers.c Isolated yields calculated based on 2.
1	2a 4-F-C6H4	10a	47
2	2k 4-OMe-C6H4	10b	56
3	2l 4-Me-C6H4	10c	64
4	2o C6H5	10d	51
5	2p 2-pyridinyl	10e	54
6	2r 3,5-dimethyl-C6H3	10f	78
7	2m 2-Me-C6H4	10g	36

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According to Maiti's excellent work, the ligand-free Cu-catalyzed chemoselective mono-arylation of aliphatic alcohols could be applied to modify Ullmann coupling reaction between diols 6 and aryl iodides 11 from commercial available 4-chloro-6-iodo-quinazoline and different anilines, thus to provide [4-phenylamino-6-quinazolinyl]-oxyl-propanol 12, a key intermediate of anticancer drug candidate EMB-3.^22,23 Under the optimized conditions, 11a–c reacted with aliphatic diols 6a–c to form the corresponding compounds successfully in 60–82% yields (Table 5, entries 1–7). And this intermediate 12 could shorten the synthesis steps of EMB-3 from 6 to 3. Furthermore, under these optimized reaction conditions, 200 g – scale synthesis (yield: 82%) of 12a, which was a key intermediate of anti-tumor compound EMB-3, was realized.

Table 5 Applied synthesis of 12 from N-phenyl-6-iodo-4-quinazolinamine 11 and aliphatic diols 6^a

Entry	11	6	12	Yield^b [%]
a Reaction conditions: 11 (0.5 mmol), 6 (1.5 mmol, 3.0 equiv.), CuI (0.05 mmol, 10 mol%), NaO^t-Bu (1.5 mmol, 3.0 equiv.), DMF (2 mL), 80 °C, 18 h.b Isolated yields calculated based on 11.
1	11a	6a		82
2	11a	6b		73
3	11a	6c		76
4	11b	6a		65
5	11b	6b		60
6	11c	6a		72
7	11c	6b		77

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On the basis of the above results and literature reports,²⁴ we formulated a possible mechanism for the copper-catalyzed tandem cyclization in Scheme 2. In the presence of a base, the chelation of CuI with diols 6 forms a reactive species 13. In this process of forming intermediate 13, diols 6 act as reactant and ligand. The ring strain of intermediate 13 is not supposed to be too strong. Herein, glycol could not react with CuI to form the transition state. Subsequent oxidative addition of intermediate 13 with aryl iodides 2 leads to the intermediate 14. Then CuI is regenerated by a putative reductive elimination, giving the desired products 7 simultaneously.

Scheme 2 Possible mechanism of copper-catalyzed O-arylation of aliphatic alcohols.

Conclusions

In summary, we have successfully developed a ligand-free Cu-catalyzed protocol to synthesize alkyl aryl ethers from multi-substituted aryl iodides and aliphatic diols under mild conditions with moderate to good yields. Furthermore, with this method, under the optimized reaction conditions, 200 g – scale synthesis (yield: 82%) of a key intermediate of medicine EMB-3 was realized.

Acknowledgements

This research was supported by Ministry of Science and Technology of China (Grant 2012ZX09103101–042).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5ra12529d

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