Aerobic Catalyzed Oxidative Cross-Coupling of N,N-Disubstituted Anilines and Aminonaphthalenes with Phenols and Naphthols

Abstract

The cross-coupling of N,N-dialkyl aniline and aminonaphthalenes with phenols and naphthols using a Cr-salen catalyst under aerobic conditions was developed. Notably, air serves as an effective oxidant affording products in high selectivity. Initial mechanistic studies suggest an outer-sphere oxidation of the aniline/aminonaphthalene partner, followed by nucleophilic attack of the phenol/naphthol. Single products were observed in most cases, whereas mixtures of C-C and C-O coupled products arising from reactions involving aminonapthalene and sterically unencumbered phenols.

Graphical Abstract

Unsymmetrical biaryls are found in organometallic chemistry,¹ natural product synthesis,² pharmaceutical synthesis,³ and materials chemistry.⁴ The ability to generate such structures selectively from simple precursors is an important challenge in organic synthesis. These motifs are classically synthesized through the metal-catalyzed cross-coupling of prefunctionalized partners.⁵ Dehydrogenative cross-coupling of arenes,⁶ particularly of phenols,^7,8 has been developed recently to overcome the need for prefunctionalization.

The 2’-aminobiphenyl-2-ol structural motif is an interesting unsymmetrical biaryl with examples found in active natural products⁹ (Figure 1). Most routes to access these structures involve prefunctionalization. Oxidative methods for direct C-H activation to construct this motif have been developed in the past decades.¹⁰ Seminal work centers on the coupling of 2-aminonaphthalene with 2-naphthol (Scheme 1a), which was complicated by the high reactivity of the amino group. More recently, oxidative couplings of N,N-disubstituted aniline derivatives with naphthols have been studied using Fe and Ce catalysts (Scheme 1b).^11a,11b The scope was confined to 2-naphthol and t-BuOOH was needed, and in the latter case elevated temperatures were required. With chiral auxiliary derived aminonaphthalenes, catalytic oxidative conditions give rise to enantiopure axial chiral versions.¹² The coupling of phenols with similar anilines is much more difficult, with the first report from Fotie et al. in 2016 (Scheme 1c).¹³ This process required super- stoichiometric Ag oxidant (3 equiv), with the highest yield of the aniline/phenol coupling being 70%. Further methods with a hypervalent iodine oxidant,¹⁴ periodic acid,¹⁵ a Pd/Al₂O₃ catalyst,¹⁶ and a heterogeneous Rh catalyst¹⁷ have been reported, but with very limited examples (3–6 per report) or the requirement of aminonaphthalenes and naphthols vs anilines and phenols. For example, an electrochemical method only uses 2-aminonaphthalene.¹⁸ Herein, we describe the development of Cr-salen catalyzed cross-coupling of N,N-substituted anilines/2-aminonaphthalenes with naphthols/phenols. This process utilizes benign conditions (rt, air as oxidant, Scheme 1d). Interestingly, most reactions result in C-C coupling products, but some couplings of 2-aminonaphthalene with phenols lead to the formation of C-O coupled products as well.

Figure 1.

Natural products with 2’-aminobiphenyl-2-ol motif.

Scheme 1.

Oxidative cross-couplings of 2-aminonaphthalenes/anilines with naphthols/phenols.

Metal-salen complexes have been shown to be powerful catalysts in oxidative reactions.^8g In particular, our group has previously reported the mechanism of a Cr-salen catalyzed phenol cross-coupling.¹⁹ To interrogate the potential of these metal-salen complexes in aniline/phenol cross-coupling, high-throughput experimentation screening was implemented with a library of catalysts. When using 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) as the solvent, every catalyst screened resulted in some level of product formation (Figure 2). To identify the best catalyst, the top leads were run again on a larger scale (see SI) which revealed that the Cr-salen complex results in the highest yield and minimizes formation of undesired side-products.

Figure 2.

High-throughput experimentation results for catalyst library screen (internal standard = 4,4’-di-tert-butylbiphenyl).

Optimization studies were performed on the cross-coupling of N,N-dimethyl-2-aminonaphthalene and 2-naphthol using this Cr-salen catalyst in HFIP (eq 1, Table 1). Lowering the temperature to rt provided higher yields (entries 1–3). Lower yields were observed at 0 °C, potentially due to decreased solubility in HFIP (entry 4). Shorter reaction times led to a slight decrease in yield, which was found to be more detrimental with less reactive coupling partners (entry 5). Different catalyst loadings (5, 10, and 20 mol %) had a small effect on yield (entries 3, 6–7). Moving toward less harsh oxidants, O₂ was found to be beneficial (entry 8), with even air being suitable for the reaction to proceed (entry 9). Finally, the reactant ratio was optimized to 1:1.5 aniline to phenol without a decrease in yield (entry 10).

Table 1.

Optimization of oxidative cross-coupling of N,N-dimethyl-2-aminonaphthalene and 2-naphthol.^a

						(1)
	1b:2a	cat (mol %)	oxidant	T (°C)	t	Yield (%)
1	1:3	10	t-BuOOH	80	1 d	33
2	1:3	10	t-BuOOH	50	1 d	51
3	1:3	10	t-BuOOH	rt	1 d	55
4	1:3	10	t-BuOOH	0	1 d	23
5	1:3	10	t-BuOOH	rt	6 h	52
6	1:3	20	t-BuOOH	rt	1 d	59
7	1:3	5	t-BuOOH	rt	1 d	52
8	1:3	10	O2	rt	1 d	78
9	1:3	10	Air	rt	1 d	73
10	1:1.5	10	Air	rt	1 d	74

^aHFIP: 1,1,1,3,3,3-hexafluoro-2-propanol. Conditions: 1b (0.10 mmol, 0.10 M), t-BuOOH (2.0 equiv), HFIP (1.0 mL). Yields obtained by ¹H NMR using 4,4’-di-tert-butylbiphenyl as internal standard.

With these optimized conditions, the scope of the method was investigated (eq 2). N,N-Dimethyl-2-aminonaphthalene was an effective coupling partner with a wide range of naphthols and phenols (Figure 3; blue compounds are new compounds, not reported previously). Few byproducts were observed and the efficiency was generally good. Bromo- and methoxynaphthols were well tolerated along with 2-naphthol (Figure 3, 3ba-3bc). Several substituted phenols coupled effectively as well (3bd-3bh), and with very high regioselectivity (>50:1). On larger scale, the reaction efficiency was even higher (3ba, 83%)

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Figure 3.

Couplings of N,N-dimethyl-2-aminonaphthalene using the conditions in eq 2 (blue compounds are new compounds, not reported previously). ^aIsolated yield at 1.0 mmol scale.

The catalyst system was sufficiently reactive that the couplings of the more difficult aniline derivatives could be accomplished (Figure 4). In addition to the N,N-dimethyl congener (3aa-3ab), para-toluidines with N,N-diethyl substitution (3ca-3cb) or with incorporation of the nitrogen into pyrrolidine (3da-3db), piperidine (3ea-3eb), or morpholine (3fb) rings all coupled with naphthols with good to very good efficiency. The more electron rich para-methoxyanilines were also coupled effectively (3ga-3ha). Notably, the coupling of the aniline analogs with phenols also proceeded in moderate yield (3dd-3de) even for a mono-substituted phenol (3ai) for which selective couplings are typically very difficult. In all of these cases, the reactions were fairly clean giving only one product along with residual starting material or decomposition to baseline materials.

Figure 4.

Couplings of anilines using the conditions in eq 2 (BRSM = based on recovered starting material; blue compounds are new compounds, not reported previously).

Coupling reactions of N,N-dimethyl-2-aminonaphthylene and phenols led to somewhat unexpected results in certain instances (Figure 5). Coupling using phenols with multiple unhindered reactive sites, such as 2-tert-butylphenol, led to a mixture of ortho- and para-substituted products (3bj,3bj’). The product ratio observed (1:2.2) is consistent with calculated site nucleophilicities of the ortho- and para-positions of the phenolate (1.70:2.15)¹⁹ of the phenol showing a preference for para-substituted product. When using a phenol with a sterically unencumbered -OH group, a mixture of C-C (3bi-3bn)and C-O (3bi’−3bn’) coupled products were observed. In para-substituted phenols (3bi-3bl), a preference for C-O product is observed, with product ratios of 1:1.5–3.1. For each of these cases, the site nucleophilicities (see SI) of the phenolates predict that the oxygen is more reactive in accord with the observed trends. The greatest preference for C-O products is seen with an electron-donating methoxy group (3bl,3bl’). In contrast, increasing the steric bulk around the OH leads to more C-C coupled product (3bm). Furthermore, increased steric bulk around the ortho-positions (by 3,5-substitution) led to a greater preponderance of C-O product (3bn’).

Figure 5.

Couplings of N,N-dimethyl-2-aminonaphthalene with two outcomes (C-C_ortho vs C-C_para or C-C vs C-O; blue compounds are new compounds, not reported previously).

This method required certain structural and electronic parameters in order for coupling to occur. Specifically, para-substitution of the aniline derivative is required. N,N-Dimethylaniline as well as ortho-substituted N,N-dimethylanilines did not undergo coupling with this method. Further, electron-withdrawing substituents on the aniline or phenol partner were not tolerated. The incorporation of the nitrogen into a ring (e.g. N-methylpyrrole or N-methylindole) did not afford cross-coupled product using this method.

To gain greater insight into the reaction, the active catalyst of the system was determined. The addition of 100 mol % oxo-Cr(V) was found to result in 100% conversion of starting material. Addition of sterically hindered base (2,6-di-tert-butyl-4-methylpyridine) increased the rate of loss of oxo-Cr(V) (1 min vs 20 s). This finding is consistent with reported work on the cross-couplings of phenol with the same Cr-salen catalyst.¹⁹

Cyclic voltammetry and calculated nucleophilicities were used to probe which substrate likely initiates the reaction. The onset oxidation potential of N,N-dimethyl-2-aminonaphthalene (0.33 eV, relative to Fe/Fe⁺) was found to be significantly lower than the most oxidizable phenolic partner, 2,6-dimethoxyphenol (0.89 eV)¹⁹ suggesting the aminonaphthalene was the more oxidizable species in the reaction. Support for this oxidation order is the rapid quantitative formation of a homo-dimer when N,N-dimethyl-2-aminonaphthalene alone is subjected to the catalyst.

Free radical inhibitor butylated hydroxytoluene (BHT, 1.06 eV) was found to alter the reaction outcome dramatically. When N,N-dimethyl-2-aminonaphthalene (eq 3, no phenol present except BHT) was subjected to the Cr-salen catalyst under air with BHT, the aminonaphthalene homo-coupling that was otherwise observed (see above) was completely suppressed and compound 4 was formed instead.

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Based on the above data, a catalytic cycle is proposed (Figure 6). Binding of the sterically hindered N,N-dimethyl-2-aminolnaphthalene to the Cr-salen catalyst would be disfavored²⁰ which suggests the possibility of an outer-sphere oxidation occurring in the reaction. Such an oxidation by the oxo-Cr(V) species II would yield a radical cation and Cr(IV) species III. A computational study of the site nucleophilicities¹⁹ of the coupling partners revealed the deprotonated phenol/naphthol (1.67–2.88, see SI and previous work¹⁹) partner is considerably more nucleophilic at the ortho-carbon than N,N-dimethyl-2-aminonaphthalene (0.95). Thus, after deprotonation of the phenol by III, attack of the more nucleophilic phenolate onto the radical cation accompanied by a one-electron oxidation would induce selective cross coupling and yield IV. Addition of base suppresses formation of the aminonaphthalene homo-dimer by about 6% in the cross-coupling of N,N-dimethyl-2-aminonaphthalene and 4-chlorophenol, which further supports the role of the phenolate anion. No enantioselectivity was observed in the couplings of 3ba, 3bb, and 3bc (see SI) which is consistent with a mechanism where coordination of the phenol does not occur. Ultimately, tautomerization and water release leads to the product and regenerates the Cr(III)-salen catalyst I. The complementary nature of the coupling partners (oxidizability vs nucleophilicity) is similar to that invoked in some phenol cross-couplings.^8d

Figure 6.

Proposed catalytic cycle for oxidative cross-coupling.

For some cases (i.e. unhindered phenols), phenol oxidation may involve coordination to the Cr(IV) species III and inner sphere electron transfer; however, dissociation of the resulting phenoxyl equivalent needs to be invoked to explain the C-O coupling outcomes (Figure 5). For more hindered phenols (e.g. 2,6-di-tert-butylphenol), outer sphere electron transfer appears more likely.

In conclusion, we have developed an effective catalytic oxidative cross-coupling of N,N-disubstituted aniline derivatives with naphthols and phenols. The method proceeds under benign conditions, using O₂ in air as the oxidant at room temperature. Mechanism experiments suggest oxidation of the aniline portion occurs first, which then engages in a coupling with the more nucleophilic species (naphthol/phenol) at the more nucleophilic site via a Cr(V) to Cr(III) redox couple.