Atroposelective Synthesis of 2,2′‐Bis(arylamino)‐1,1′‐biaryls by Oxidative Iron(III)‐ and Phosphoric Acid‐Catalyzed C−C Coupling of Diarylamines

Abstract

We describe an iron‐catalyzed asymmetric oxidative C−C coupling of diarylamines which proceeds at room temperature with air as final oxidant. Using hexadecafluorophthalocyanine‐iron(II) as catalyst in the presence of catalytic amounts of an axially chiral biaryl phosphoric acid, the resulting chiral 2,2′‐diamino‐1,1′‐biaryls are obtained in up to 90 % ee as confirmed by chiral HPLC. A detailed mechanism has been proposed with a radical cation‐chiral phosphate ion pair as key intermediate leading to the observed asymmetric induction.

The asymmetric oxidative C−C homocoupling reaction of diarylamines using air as final oxidant is catalyzed by a hexadecafluorinated iron‐phthalocyanine complex and an axially chiral biaryl phosphoric acid. A radical cation‐chiral phosphate anion pair is proposed as key intermediate responsible for the asymmetric induction.

Introduction

Sterically constrained, atropisomeric biaryl motifs are found in many biologically active natural products,[ ¹ , ² ] drugs,[ ³ , ⁴ , ⁵ ] materials,[ ⁶ , ⁷ , ⁸ ] as well as in catalysts ^[9] and ligands,[ ¹⁰ , ¹¹ , ¹² ] which have been used for asymmetric synthesis. Therefore, diverse methods have been developed for the enantioselective synthesis of biaryl atropisomers (Scheme 1). ^[13]

Scheme 1.

Catalytic asymmetric syntheses of 2,2′‐dihydroxy‐1,1′‐biaryls (a) and 2,2′‐diamino‐1,1′‐biaryls (b−e). HX*=chiral Brønsted acid.

Direct asymmetric oxidative coupling reactions represent the most elegant procedures and have been extensively studied for the synthesis of chiral 2,2′‐dihydroxy‐1,1′‐biaryls (Scheme 1a). ^[14] Most of them are using copper ^[15] or vanadium ^[16] catalysts. Iron catalysts are attractive since they are cheap and environmentally benign. ^[17] Therefore, several iron‐catalyzed asymmetric oxidative biaryl coupling reactions have been reported recently. ^[18] For the synthesis of racemic 2,2′‐diamino‐1,1′‐biaryl compounds, oxidative C−C coupling procedures have also been explored (Scheme 1b). ^[19] However only for the synthesis of unsubstituted 1,1′‐binaphthyl‐2,2′‐diamine (BINAM), asymmetric procedures using stoichiometric amounts of copper ^[20] or catalytic amounts of vanadium ^[16a] are known. Moreover, chiral Brønsted acid‐catalyzed benzidine rearrangements of 1,2‐diarylhydrazines (Scheme 1c) ^[21] or chiral Lewis acid‐catalyzed coupling reactions of azo compounds (Scheme 1d) ^[22] provide asymmetric routes to 2,2′‐diamino‐1,1′‐biaryls. Our previous results have shown that Brønsted acids are promoting the hexadecafluorophthalocyanine‐iron(II)‐catalyzed (FePcF₁₆) ^[23] (Figure 1) oxidative C−C homocoupling of diarylamines, ^[24] hydroxycarbazoles, ^[25] triarylamines, ^[26] as well as the C−C cross‐coupling of tertiary anilines with hydroxyarenes, ^[27] and the C−N coupling of phenothiazines with tertiary arylamines. ^[28] Based on this, we have developed an atroposelective C−C coupling of N‐aryl‐2‐naphthylamines and diarylamines, using a chiral Brønsted acid (HX*) as co‐catalyst for the asymmetric induction (Scheme 1e). The obtained 2,2′‐diamino‐1,1′‐biaryls can serve as precursors for asymmetric syntheses. ^[29]

Figure 1.

Structure of hexadecafluorophthalocyanine‐iron(II) (FePcF₁₆).

Prerequisite for a regio‐ and stereoselective oxidative coupling is an appropriate substitution pattern of the substrate (Figure 2a). Two scaffolds meeting these conditions are the N‐aryl‐2‐naphthylamines 1 and the diarylamines 2 (Figure 2b), the latter being methylated derivatives of the substrates used for our iron‐catalyzed oxidative biaryl coupling. ^[24] The N‐aryl‐2‐naphthylamines 1 are readily prepared from 2‐naphthol and anilines by sulfonic acid‐catalyzed nucleophilic substitution. ^[30] The diarylamines 2 are synthesized from 2,3‐dimethylphenol and the corresponding arylamines via a four‐step sequence of silylation, regioselective borylation, ^[31] bromodeborylation, ^[32] and Buchwald−Hartwig amination ^[33] (see Supporting Information).

Figure 2.

a) Prerequisites for a regio‐ and atroposelective oxidative C−C coupling of diarylamines; b) two structural motifs meeting these conditions.

Results and Discussion

The oxidative homocoupling of N‐phenyl‐2‐naphthylamine (1 a) was used as model system for the optimization of the reaction conditions of the asymmetric catalysis (Table 1). Using methanesulfonic acid as co‐catalyst under ambient air, racemic 2,2′‐bis(phenylamino)‐1,1′‐binaphthyl (3 a) (Figure 3) ^[34] was obtained in 51 % yield along with 11 % of 7‐phenyl‐7H‐dibenzo[c,g]carbazole (4 a) ^[35] (Table 1, entry 1). The formation of carbazoles as by‐product is remarkable since this class of compounds has attracted a lot of interest for functional materials and as natural product framework. ^[36] A series of different chiral Brønsted acid catalysts was tested for the asymmetric induction of the homocoupling of compound 1 a (Table 1, entries 2–16). The BINOL‐derived 3,3′‐bis(triphenylsilyl)‐substituted phosphoric acid 5 f provided the highest enantiomeric excess (36 % ee of the R enantiomer) and 78 % yield for 3 a (Table 1, entry 7). A scale‐up (2.0 mmol) of this experiment afforded 3 a in only slightly lower yield (66 %) but with the same enantiomeric excess and allowed an almost complete reisolation of the chiral Brønsted acid catalyst 5 f (Table 1, entry 17). Only one recrystallization step was required to afford (R)‐3 a in 98 % ee as confirmed by chiral HPLC and by the value for the specific optical rotation (see Supporting Information). The absolute configuration of compound 3 a was assigned based on a comparison of the specific optical rotation with the corresponding value reported previously by Kočovský et al. ^[29a]

Table 1.

Optimization of the reaction conditions for the asymmetric iron‐catalyzed oxidative C−C coupling reaction of N‐phenyl‐2‐naphthylamine (1a).^[a]

Entry	HX	t [h]	Yield [%]			3 a: ee [%][b]
			3 a	4 a	1 a
1[c]	MsOH	0.5	51	11	7	0
2	5 a	1.5	62	8	16	26 (R)
3	5 b	1.5	71	12	‐	8 (R)
4	5 c	1.5	48	‐	26	17 (R)
5	5 d	3	82	13	‐	22 (R)
6	5 e	5	67	17	‐	3 (R)
7	5 f	5	78	9	‐	36 (R)
8	5 g	6	83	11	‐	19 (R)
9	5 h	7	45	4	34	24 (R)
10	5 i	6	37	13	50	7 (R)
11	5 j	2	54	7	10	25 (S)
12	5 k	7	46	9	9	28 (S)
13	5 l	3	49	21	15	15 (S)
14	5 m	4.5	50	16	27	15 (R)
15	5 n	8	54	5	14	5 (R)
16	(+)‐CSA	5.5	43	26	‐	∼0
17[d]	5 f	6	66	7	6	36 (R)[e]

[a] Reaction conditions: 1 a (0.1 mmol), FePcF₁₆ (3 mol%), HX (10 mol%), CH₂Cl₂, rt, air (1 atm). [b] Determined by chiral HPLC (see Supporting Information). [c] 1 a (0.4 mmol). [d] 1 a (2.0 mmol), 97 % 5 f reisolated. [e] 98 % ee after one recrystallization from MeCN.

Figure 3.

Molecular structure of the biaryl compound rac‐3 a in the crystal (thermal ellipsoids are shown at the 50 % probability level).

Next, we have explored the scope of the reaction for the iron‐catalyzed asymmetric (method A) and non‐asymmetric (method B) oxidative coupling of the N‐aryl‐2‐naphthylamines 1 b–1 g to the 2,2′‐bis(arylamino)‐1,1′‐binaphthyls 3 b–3 g (Scheme 2). The oxidative homocoupling of compound 1 b showed that using 30 mol % of the chiral Brønsted acid 5 f led to more reliable results. Compared to the parent compound 1 a (Table 1, entry 7), the ortho‐substituents in the diarylamines 1 b and 1 c led to an increased enantiomeric excess of the resulting coupling products 3 b and 3 c, whereas the para‐substitution of the substrates 1 d–1 f obviously has the reverse effect. The nitro substituent of compound 1 g slows down the reaction significantly and thus diminishes the turnover. The asymmetric coupling reactions catalyzed by chiral phosphoric acids (method A) are proceeding much more slowly as compared to the reaction catalyzed by methanesulfonic acid (method B). However, for the asymmetric coupling the yield of the biaryl compound is higher and less N‐aryldibenzo[c,g]carbazole 4 is formed. Both effects can be ascribed to the lower acidity of the phosphoric acid but also to steric hindrance of the chiral phosphate counterion. This influence of a bulky anion might be useful for improving the yields and selectivities of such transformations proceeding via radical cation intermediates.

Scheme 2.

Iron‐catalyzed oxidative C−C coupling reaction of the N‐aryl‐2‐naphthylamines 1. Method A (asymmetric): FePcF₁₆ (3 mol %), 5 f (30 mol %), CH₂Cl₂, rt, air (1 atm). Method B (non‐asymmetric): FePcF₁₆ (3 mol %), MsOH (10 mol %), CH₂Cl₂, rt, air (1 atm). [a] 5 f (10 mol %). [b] Catalyst: 5 a (10 mol %). Result with 10 mol % of catalyst 5 f (21 h): 19 % 3 g (29 % ee), 11 % 4 g, 31 % 1 g.

Generally, better yields and higher ee values were obtained for the iron‐catalyzed asymmetric oxidative coupling of the diarylamines 2 to the corresponding biaryl compounds 6 by using only 10 mol % of the chiral Brønsted acid catalyst 5 f (Scheme 3). An ortho‐substitution increased the asymmetric induction but concomitantly decreased the turnover as shown by the syntheses of 6 b and 6 e, which were obtained in 84 % and 90 % ee, respectively. The o‐phenyl‐substituted diarylamine 2 d gave no product in the presence of the phosphoric acid 5 f, whereas with methanesulfonic acid a fast conversion to racemic 6 d was observed.

Scheme 3.

Iron‐catalyzed oxidative C−C coupling reaction of the diarylamines 2. Method A (asymmetric): FePcF₁₆ (3 mol %), 5 f (10 mol %), CH₂Cl₂, rt, air (1 atm). Method B (non‐asymmetric): FePcF₁₆ (3 mol %), MsOH (10 mol %), CH₂Cl₂, rt, air (1 atm).

In order to rationalize the asymmetric induction of the biaryl bond formation by the chiral phosphoric acid, we have proposed a mechanism proceeding via a radical cation‐chiral phosphate ion pair II (Scheme 4a). The hexadecafluorophthalocyanine‐iron(II) complex ([Fe(II)]) is oxidized by molecular oxygen, giving water and the iron(III) phosphate (iron catalytic cycle, red). The iron(III) species oxidizes the diarylamine I to give an organic radical cation‐chiral phosphate ion pair II, ^[37] thus regenerating the iron(II) complex. Reaction of the radical cation II with an additional molecule of diarylamine I affords the C−C‐coupled intermediate III. Deprotonation by the phosphate counterion regenerates the phosphoric acid (phosphate catalytic cycle, blue) and provides the radical intermediate IV. Further oxidation of IV by an iron(III) phosphate (second iron catalytic cycle, red) leads to the ion pair V. Subsequent deprotonation of V by the phosphate ion finally gives the biaryl product VI. Several possibilities can be envisioned for the asymmetric induction, for example an asymmetric C−C‐coupling reaction of the radical cation‐chiral phosphate ion pair II with the diarylamine I, ^[38] or a central‐to‐axial chirality transfer during the deprotonation of the centrally chiral intermediates III and V by the chiral phosphate counterion. ^[39] As an alternative mechanism, the homocoupling of two organic radical cation‐chiral phosphate ion pairs II and subsequent twofold deprotonation to the biaryl product VI could be considered.

Scheme 4.

a) Proposed mechanism for the iron‐catalyzed asymmetric C−C coupling of diarylamines; b) proposed mechanism for the formation of the N‐arylcarbazole by‐product.

The formation of the N‐arylcarbazoles is explained by an intramolecular nucleophilic addition of the amine to the iminium carbon atom at the stage of intermediate V (Scheme 4b). Subsequent aromatization of the resulting aminal VII by β‐elimination provides the N‐arylcarbazole VIII along with the corresponding anilinium phosphate.

Conclusion

In summary, we have developed an asymmetric iron‐catalyzed oxidative C−C coupling of N‐aryl‐2‐naphthylamines and diarylamines to the corresponding biaryl compounds using air as final oxidant. The asymmetric induction has been achieved by an axially chiral biaryl phosphoric acid as co‐catalyst. Steric hindrance caused by bulky substituents at the ortho‐positions of the aryl ring which is not coupled leads to asymmetric inductions of up to 90 % ee, whereas the influence of substituents at the meta‐ and para‐position of this aryl ring is less pronounced. A radical cation‐chiral phosphate ion pair has been proposed as key intermediate of this asymmetric coupling.

Conflict of interest

The authors declare no conflict of interest.

Supporting information

As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re‐organized for online delivery, but are not copy‐edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors.

Supporting Information

Fritsche R. F., Schuh T., Kataeva O., Knölker H.-J., Chem. Eur. J. 2023, 29, e202203269.

Data Availability Statement

The data that support the findings of this study are available in the supplementary material of this article.