Synthesis of meta-Aminophenol Derivatives via Cu-Catalyzed [1,3]-Rearrangement—Oxa-Michael Addition Cascade Reactions

Abstract

Cu-catalyzed reactions of N-alkoxy-2-methylanilines and alcohols in the presence of catalytic amounts of IPrCuBr and AgSbF₆ afforded the corresponding meta-aminophenol derivatives in good to high yields. These reactions proceed via a [1,3]-rearrangement, in which the alkoxy group migrates from the nitrogen atom to the methyl-substituted ortho position, followed by an oxa-Michael reaction of the resulting ortho-quinol imine intermediate.

1. Introduction

meta-Aminophenol derivatives are frequently used in pharmaceutical science (Figure 1) [1,2,3,4,5]. For example, SEA0400 exhibits inhibitory activity on the Na⁺/Ca²⁺ exchanger [1], while tetrapetalone A [2] and tenaspimycin [3] inhibit lipoxygenase and Hsp90, respectively. However, performing the synthesis of meta-aminophenol scaffolds in an efficient and selective manner has been challenging because electrophilic substitution reactions, the most common approach to the functionalization of anilines and phenols, exhibit ortho/para preference. The radical hydroxylation of nitrobenzene, which occurs at the meta position, has significant drawbacks in terms of regioselectivity, reaction efficiency, and functional group compatibility (Figure 2a) [6,7,8]. The enzymatic oxidation of nitrobenzene can synthesize meta-nitrophenol with excellent site-selectivity, although this method suffers from the poor generality of substrates [9]. In this regard, transition metal-catalyzed cross-coupling reactions using meta-haloanilines and meta-halophenols are among the most frequently employed methods (Figure 2b) [10,11,12,13,14,15]. For example, Buchwald–Hartwig amination reactions of meta-halophenol derivatives using palladium catalysts [10,11,12,13] and Ullman-type reactions using copper catalysts [14,15] have been frequently used for the synthesis of meta-aminophenol derivatives. Catalytic C–O bond-forming reactions using meta-haloanilines have also been employed as an alternative approach to cross-coupling reactions by employing various transition metal catalysts, such as palladium [16,17], copper [18,19], nickel [20], and gold [21]. However, these reactions are also inherently associated with the selectivity issue in meta-haloaniline/phenol preparations. Although other approaches to functionalized meta-aminophenol derivatives have been recently reported [22], the development of efficient and robust methods for the synthesis of multiply substituted meta-aminophenol derivatives is a pressing issue.

Against this backdrop, we designed cascade reactions, including the Cu-catalyzed [1,3]-rearrangement, as a potential approach to overcome issues related to selectivity (Figure 3) [23,24,25,26,27,28,29,30,31,32]. We have recently reported that N-heterocyclic carbene (NHC)-ligated cationic copper catalysts efficiently promote the [1,3]-rearrangement of N-alkoxyanilines [23,24,25,26,27]. Specifically, N-alkoxyanilines 1 having an electron-donating group (EDG) at the ortho position selectively generated functionalized ortho-quinol imine intermediates A via a [1,3]-rearrangement of the alkoxy group to the EDG-substituted ortho position [25,26,27,28]. ortho-quinol imine intermediates A underwent favorable transformations, including a [1,2]-rearrangement (Figure 3a) [25]; a Michael addition with carbon nucleophiles such as N-methylindole, 1,3,5-trimethoxybenzene, and dimethyl malonate (Figure 3b) [26]; and a Diels–Alder reaction with electron-rich and electron-deficient olefins [27]. It should be emphasized that the Cu-catalyzed [1,3]-rearrangement can generate functionalized quinol imine intermediates A, which had been inaccessible via conventional methods, such as thermally induced rearrangement [33] and oxidation [34]. Accordingly, we envisioned that the reactions with alcohols as oxygen nucleophiles would give functionalized meta-aminophenol derivatives in a selective manner through an oxa-Michael addition of generated ortho-quinol imine intermediates A (Figure 3d) [35,36]. Here, we report the Cu-catalyzed [1,3]-rearrangement—oxa-Michael addition—aromatization cascade reactions of N-alkoxyanilines 1 and alcohol nucleophiles 2, which afforded meta-aminophenol derivatives 3 in good-to-acceptable yields (Figure 4).

2. Results and Discussion

Initially, the reaction of N-methoxy-2-methylaniline 1a having a p-trifluoromethylbenzoyl group on the nitrogen atom and one equivalent of methanol 2a in the presence of catalytic amounts of IPrCuBr [IPr: N,N′-bis(2,6-diisopropylphenyl)-imidazol-2-ylidene, 10 mol%] and AgSbF₆ (10 mol%) in chlorobenzene at 70 °C afforded a mixture of the following four regioisomers: desired 6-methyl-3-anisidine 3aa; 2-methyl-3-anisidine 4aa, which was derived from the oxa-Michael addition to the meta position next to the ortho-methyl group; 3-methyl-2-anisidine 5a, which was derived from domino [1,3]/[1,2]-rearrangement reactions [25]; and 6-methyl-2-anisidine 6a, which was derived from the [1,3]-rearrangement reactions of the methoxy group to the unsubstituted ortho position (namely, [1,3]′-rearrangement) to generate ortho-quinol imine intermediate 7a′ (Scheme 1). Attempts to optimize the reaction conditions to selectively synthesize 3aa were unsuccessful.

To reduce the number of regioisomers prior to the optimization of reaction conditions, we preliminary screened several starting materials 1. To our delight, the reaction of substrate 1b having a fluorine atom at the para position of the aniline ring at 70 °C generated two regioisomers, 3ba and 6b. Among the NHC ligands examined, IPr exhibited the best reactivity and product selectivity (

Table 1. Optimization of reaction conditions.

Entry	NHC·CuX	AgX′	Solvent	Temp. (°C)	3ba (%) a	6b (%) a	1b (%) a
1	IPrCuBr	AgSbF6	PhCl	70	70	28	<1
2	IMesCuCl	AgSbF6	PhCl	70	21	3	76
3	SIPrCuCl	AgSbF6	PhCl	70	13	5	47
4	IPrCuBr	AgBF4	PhCl	70	43	13	37
5	IPrCuBr	AgNTf2	PhCl	70	<10	<15	- b
6	IPrCuBr	AgSbF6	DCE	70 c	76	22	<2
7	IPrCuBr	AgSbF6	toluene	70	63	18	11
8	IPrCuBr	AgSbF6	1,4-dioxane	70	59	19	7
9	IPrCuBr	AgSbF6	EtOAc	70	29	12	38
10	IPrCuBr	AgSbF6	DCE	60 d	<78	18	3
11	IPrCuBr	AgSbF6	DCE	80 e	75	22	6
12	IPrCuBr	-	DCE	70	<1	<1	99
13	-	AgSbF6	DCE	70	<1	<1	92

^{a 1}H NMR yields using CH₂Br₂ as the internal standard. ^b The yield was not determined, but a considerable amount of 1b was recovered; ^c 17 h; ^d 40 h; ^e 10 h.

, entry 1), whereas the use of IMes [1,3-Bis(2,4,6-trimethylphenyl)-1,3-dihydro-2H-imidazol-2-ylidene] and SIPr [1,3-bis(2,6-diisopropylphenyl)imidazolidine] resulted in low catalytic activity (entries 2 and 3). The reactivity was significantly affected by counteranions; less coordinative counteranions such as hexafluoroantimonate were effective for the present transformations. On the other hand, when AgBF₄ and AgNTf₂ were used instead of AgSbF₆, 3ba was formed in low chemical yields along with a considerable amount of recovered 1b (entries 4 and 5). The reaction in 1,2-dichloroethane (DCE) proceeded quickly to afford product 3ba in the best yield among the solvents examined (entries 6–9). Neither the chemical yield nor the product selectivity was improved when the temperature of the reaction of 1b and 2a was changed from 70 °C to 60 °C and 80 °C, respectively (entries 10 and 11). The reaction in the absence of either Cu or Ag did not yield desired product 3ba; N-methoxyaniline 1b was quantitatively recovered (entries 12 and 13).

The protecting group on the nitrogen atom significantly affected the product selectivity (

Table 2. Optimization of the protecting group of 1 and the molar amount of methanol 2a.

Entry	1	R	2a (Equiv)	3 (%) a	6 (%) a	1 (%) a
1 b	1c	Bz	1	3ca (73)	6c (12)	<1
2	1d	Cbz	1	3da (72)	<1	<1
3	1e	Troc	1	3ea (54)	<1	27
4	1f	Alloc	1	3fa (26)	6f (6)	32
5	1d	Cbz	2	3da (48)	6d (4)	46
6	1d	Cbz	5	3da (18)	6d (3)	29
7	1d	Cbz	0.5	3da (50)	6d (3)	<31
8 d	1d	Cbz	0.5	3da (71)	6d (9)	<11
9 e	1d	Cbz	1	3da (85) c	<1	<1

^{a 1}H NMR yields using CH₂Br₂ as the internal standard. The reactions were conducted on a 0.2 mmol scale; ^b 17 h. ^c Isolated yield. ^d At 80 °C. ^e The reaction was conducted at a 0.5 mmol scale.

, entries 1–4); desired meta-anisidines 3 were obtained with better product selectivity with carbamate-type protecting groups (entries 2–4) than with the amide-type protecting groups (Table 1 entry 6, and Table 2, entry 1). The use of one equivalent of methanol 2a was effective, whereas the use of a large excess (five equivalents) of methanol 2a diminished the catalytic activity (entry 2 versus entry 6). It should be noted that the reaction using half an equivalent of methanol at 80 °C afforded 3da in the 71% yield, suggesting that the methoxy group eliminated from substrate 1d participated in the reaction as a nucleophile (entry 8). Finally, the chemical yield was improved by increasing the scale from 0.2 mmol to 0.5 mmol (entry 9, Appendix A).

The optimized conditions (Table 2, entry 9) were applied to the reactions of various N-methoxyanilines 1, as summarized in

Table 3. Cu-catalyzed reactions of N-methoxyanilines 1g-m and methanol 2a ^a.

Entry	1	R	Temp (°C)	3 (%) b	1 (%) c	Byproduct (%) c
1 d,e	1g	Me	70	3ga (64)	<1	5g (<3)
2 e	1h	Ph	70	3ha (45)	<1	5h (28), 6h (27)
3	1i	Cl	70	3ia (23)	36
4 f	1i	Cl	70	3ia (30)	19
5 e,f,g	1i	Cl	90 c	3ia (61)	<1
6	1j	Br	70	3ja (40)	32
7 f	1j	Br	70	3ja (60)	<1
8 f	1k	I	70	3ka (42)	6	5k (8)
9 g,h	1l	-CºCPh	90	3la (28)	<1
10 g,i	1m	CO2Me	90	<1	9	5m (80)

^a The reaction of 1 (0.5 mmol) and 2a (0.5 mmol) was carried out in the presence of IPrCuBr (10 mol%) and AgSbF₆ (10 mol%) in DCE at 70 °C for 18 h. ^b Isolated yields. ^{c 1}H NMR yields using CH₂Br₂ as the internal standard. ^d The reaction was conducted at a 2.0 mmol scale; ^e 18 h; ^f 20 mol% IPrCuBr and 20 mol% AgSbF₆ were used. ^g Chlorobenzene was used, instead of DCE; ^h 48 h; ⁱ 24 h.

. The reactions of substrates 1g and 1h, having a methyl and a phenyl group, respectively, at the para position, proceeded at 70 °C, affording corresponding meta-anisidines 3ga and 3ha in good yields (entries 1 and 2). Substrate 1j, having a bromo group, was converted into desired product 3ja when the loading amount of the Cu catalyst was increased (20 mol%, entry 7). The chemical yield of 3ia, which has a chloro group at the para position, was slightly improved when the reaction was performed at 90 °C using chlorobenzene instead of DCE as the solvent (entries 3–5). An iodo group (1k) was tolerated under the present reaction conditions, affording multi-substituted meta-aminophenol derivative 3ka in an acceptable yield (entry 8). 3-Anisidine 3la, which has an alkynyl group at the para position of the nitrogen atom, could also be generated (entry 9). In contrast, substrate 1m having a methoxycarbonyl group at the para position, exclusively afforded domino-rearrangement byproduct 5m (entry 10). The reaction of N-ethoxyaniline 1n and ethanol 2b afforded corresponding 3-ethoxyaniline 3nb in a good yield (Scheme 2).

The reaction of N-methoxyaniline 1d and one equivalent of 2-phenethyl alcohol 2c afforded 3-phenylethoxyaniline 3dc in a 51% yield, along with 3da, which was produced through the oxa-Michael addition of methanol derived from 1d, in a 14% yield (

Table 4. Cu-catalyzed reactions of N-methoxyanilines 1d and alcohols 2.

Entry	2	ROH	3 (%) a	3da (%) a
1	2c	PhCH2CH2OH	3dc (51)	14
2	2c b	PhCH2CH2OH	3dc (51)	7
3	2d	H2C=CHCH2OH	3dd (35)	23
4	2e	tBuOH	- c	- c
5	2f	PhOH	- c	- c

^a The reaction of 1d (0.5 mmol) and 2 (0.5 mmol) was carried out in the presence of IPrCuBr (10 mol%) and AgSbF₆ (10 mol%) in PhCl at 90 °C for 42 h. ^b Two equivalents of 2c were used. ^c A mixture of unidentified products was obtained.

, entry 1). The use of two equivalents of 2c did not improve the product selectivity (entry 2). The reaction of 1d and allyl alcohol 2d also afforded 3-allyloxyaniline 3dd as the major product (entry 3). These results suggest that substrates 1 react more preferentially with external alcohols 2c and 2d than with methanol 2a derived from 1, although the product selectivity depends on the structure of 2. When tert-butanol (2e) and phenol (2f) were employed as an alcohol nucleophile, the reactions gave a mixture of unidentified products (entries 4 and 5).

A proposed mechanism for the Cu-catalyzed reactions of N-methoxyanilines 1 and alcohol nucleophiles 2 is illustrated in Figure 5a. The cationic copper catalyst coordinates to 1 to form chelate complex 8, and this is followed by an oxidative addition of the N–O bond to the Cu(I) catalyst to form Cu(III) complex 9 [29]. Because of the contribution of canonical form 9′, a C–O bond is formed at the methyl-substituted ortho position, generating ortho-quinol imine intermediates 10 that coordinate to the cationic Cu catalyst. Electrophilically activated ortho-quinol imine intermediates 10 undergo nucleophilic addition of 2 to form Cu enamide species 11. Finally, proton transfer and elimination of methanol 2a give products 3 along with the regenerated cationic Cu catalyst. Byproducts 5 are formed via a Cu-catalyzed [1,2]-rearrangement of ortho-quinol imine intermediates 12 [25]. The product selectivity of the present reaction system was greatly influenced by the para substituent; a fluorine atom (1d) was effective in suppressing the formation of the domino [1,3]/[1,2]-rearrangement product (5, Table 2, entry 9). This is possibly because the mesomeric electron-donating effect of the fluorine atom increases the electron density of the carbon next to the quaternary carbon in ortho-quinol imine intermediates 10d/10d′, decelerating the [1,2]-rearrangement of the methyl group (Figure 5(bi)). In contrast, when an ester group was present, the selective formation of the domino rearrangement product (5m) occurred even in the presence of methanol (Table 3, entry 10), presumably because of the undesired [1,2]-rearrangement reaction facilitated by the electron-withdrawing effect (Figure 5(bii)). In addition, because substrate 1m reacted with stronger carbon nucleophiles, such as 1,3,5-trimethoxybenzene, via [1,3]-rearrangement/Michael addition [26], the low nucleophilicity of alcohols 2 also causes the selective formation of byproduct 5m. Our preliminary DFT calculations for the [1,2]-rearrangement of para-substituted ortho-quinol imine intermediates 10 were in good agreement with these experimental results (Figure 5c). The reaction of N-methoxyaniline 1d and alcohol 2c afforded 3dc (51%) in a higher yield than 3da (14%) derived from the reaction of 1d and generated methanol 2a (Table 4, entry 1). Because the product selectivity is dependent on the structure of external alcohols 2c and 2d, the elimination of methanol 2a from enamide intermediates 11 may be mediated by external alcohol 2, affecting the concentration of methanol 2a. Further investigations to understand the reactivity of key intermediates 10 are under way in our laboratory.

3. Materials and Methods

The general procedure for the Cu-catalyzed reactions of N-methoxyaniline 1d and methanol 2a is as follows: DCE (1.0 mL) and methanol 2a (20.3 μL, 0.5 mmol) were added to a mixture of IPrCuBr (26.6 mg, 0.05 mmol), AgSbF₆ (24.0 mg, 0.05 mmol), and 1d (144.8 mg, 0.5 mmol) under an argon atmosphere, and the mixture was stirred at 70 °C for 48 h. After complete consumption of 1d, as monitored via TLC, the mixture was passed through a pad of silica gel with ethyl acetate (50 mL). The solvents were removed in vacuo, and the crude product was purified via silica gel column chromatography using hexane/ethyl acetate (20/1) as an eluent to afford 3da (123.3 mg, 0.426 mmol, 85% yield) in an analytically pure form (Supplementary Materials).

4. Conclusions

In conclusion, we have developed a new approach to prepare meta-aminophenol derivatives via Cu-catalyzed cascade reactions involving [1,3]-rearrangement, oxa-Michael addition, and aromatization in an efficient manner. Because a variety of functional groups are tolerated in this transformation, the present method is potentially useful for synthesizing a new class of meta-aminophenol derivatives.