Palladium-Catalyzed Dearomative syn-1,4-Diamination

Abstract

Herein we report a dearomative syn-1,4-diamination protocol using simple nonactivated arenes and amines. This one-pot method utilizes arene–arenophile para-cycloadducts, formed via visible-lightmediated [4+2]-photocycloaddition that undergoes formal allylic substitution with amine nucleophiles under Pdcatalysis. The products are obtained with exclusive syn-1,4-selectivity; the method permits enantioselective desymmetrization of naphthalene, as well as elaborations of amine-containing drug molecules. Furthermore, the resulting unsaturated products are amenable to numerous options for diversification. Overall, this novel dearomative functionalization strategy offers rapid and straightforward access to complex building blocks, which are difficult to prepare otherwise, from simple arenes.

Dearomatization represents one of the most prominent and effective complexity-generating strategies,¹ as it directly converts aromatic building blocks into functionalized, high-value added compounds.² In addition to the venerable Birch reduction³ and dearomative oxidation of phenols,⁴ the field has witnessed numerous developments in recent years, mainly in the area of stoichiometric transition-metal-mediated dearomatizations⁵ and catalytic dearomative elaborations of phenols and heterocycles.⁶ However, such transformations involving nonactivated arenes are widely underdeveloped and catalytic methods that result in concomitant introduction of functionality are particularly scarce.⁷

Recently, we have reported several dearomative functionalization methods using small organic molecules called arenophiles,⁸ such as N-methyl-1,2,4-triazoline-3,5-dione (MTAD, 1), which can undergo visible-light-mediated para-cycloaddition with simple arenes (Figure 1a).⁹ The resulting arene–arenophile bicycles of type I provide ample opportunities for subsequent in situ catalytic functionalizations, as demonstrated with Pd- and Ni-catalyzed dearomative carboaminations.¹⁰ These transformations enable the direct introduction of multiple functionalities onto the arene, displaying a high degree of atom, step, and redox economy¹¹ compared to the traditional approaches needed for preparation of such products. Consequently, we have been interested in extending the scope of these catalytic processes, anticipating that the arenophile-mediated dearomative functionalization would also be feasible beyond carbon nucleophiles. Specifically, we postulated that the intermediate allylpalladium species (II) would be electrophilic enough to react with other nucleophiles,¹² such as neutral amines, to provide syn-1,4-aminofunctionalized unsaturated products.¹³

Figure 1.

(a) Pd-catalyzed dearomative syn-1,4-diamination (this work). (b) Examples of biologically active compounds that feature a syn-1,4-cyclohexanediamine motif.

Syn-1,4-cyclohexanediamines are important structural motifs that exist in many natural products and biologically active compounds, as exemplified by aminoglycoside antibiotic astromicin (2),¹⁴ VLA-4 antagonist tetrahydrobenzoquinoline 3,¹⁵ or fungicidal carboxamide 4¹⁶ (Figure 1b). Despite their abundance, preparation of decorated syn-1,4-cyclohexanediamines is not straightforward; thus, a more general and efficient strategy is needed for the synthesis of these compounds.¹⁷ Herein, we disclose a conceptually different approach to syn-1,4-cyclohexanediamine derivatives based on the dearomative 1,4-diamination of arenes. This process involves arenophile-mediated photochemical para-cycloaddition and subsequent palladium-catalyzed ring-opening of the resulting cycloadducts with amines (Figure 1a). A range of simple arenes and amines provided products with exclusive syn-1,4-selectivity, and high enantioselectivity was achieved in the case of naphthalene. The dearomatized products contain multiple handles amenable to further derivatizations and functional group interconversions, providing rapid access to a diverse set of highly functionalized molecules. Finally, this dearomatization process was used for structural elaboration of memantine, a drug that is used to treat Alzheimer’s disease.

Our preliminary investigations commenced with exposure of a cold solution of naphthalene (5) and MTAD (1) to visible light, followed by the addition of amine and Pd catalysts in THF and subsequent warming of the reaction mixture to 0 °C (Table 1). Thus, using CH₂Cl₂ as the solvent and Pd₂(dba)₃/PPh₃ as the catalysts, product 7a was obtained in 52% yield and as a single constitutional and diastereoisomer (entry 1). Importantly, this initial result demonstrated the feasibility of catalytic dearomative syn-1,4-diamination. Next, we turned our attention toward the evaluation of reaction parameters (see Supporting Information for full details). Probing the steric and electronic properties of monodentate phosphines, exemplified by PPhCy₂, P(o-MeC₆H₄)₃, and P(p-MeOC₆H₄)₃ (entries 2–4), as well as using bidentate dppf (entry 5), typically used in allylic substitution reactions, did not increase the yield of the desired product. Use of an alternative Pd source (entries 6 and 7) revealed that Pd(PPh₃)₄ gave a slight increase in efficiency. However, in all cases a significant amount of unreacted MTAD-naphthalene cycloadduct was observed after analyzing the crude reaction mixtures. In order to improve conversion, we kept the temperature of the ring-opening step at −20 °C and used longer reaction times, which proved highly beneficial for product formation (entries 8–10).¹⁸ Finally, using this procedure with EtOAc as the solvent provided the highest yield of product (62%, entry 10).

Table 1.

Optimization of Reaction Conditions^a

entry	[Pd] source (mol %)	solvent	solvent temp (°C)	time (h)	yield (%)b
1	Pd2(dba)3/PPh3 (2.5/6)	CH2Cl2	−50 to 0	5	52
2	Pd2(dba)3/PPhCy2 (2.5/6)	CH2Cl2	−50 to 0	5	22
3	Pd2(dba)3/P(o- MeOC6H4)3 (2.5/6)	CH2Cl2	−50 to 0	5	5
4	Pd2(dba)3/P(p- MeOC6H4)3 (2.5/6)	CH2Cl2	−50 to 0	5	44
5	Pd2(dba)3/dppf (2.5/6)	CH2Cl2	−50 to 0	5	36
6	[Pd(allyl)Cl]2/PPh3 (2.5/6)	CH2Cl2	−50 to 0	5	51
7	Pd(PPh3)4 (5)	CH2Cl2	−50 to 0	5	57
8	Pd(PPh3)4 (5)	CH2Cl2	−20	20	70
9	Pd(PPh3)4 (5)	EtCN	−20	20	70
10	Pd(PPh3)4 (5)	EtOAc	−20	20	72 (62)

^aStandard reaction conditions: MTAD (1, 0.5 mmol, 1.0 equiv), naphthalene (5, 1.0 mmol, 2.0 equiv), solvent (0.1 M), visible light, −50 °C, 12 h; then addition of BnNHMe (1.0 mmol, 2.0 equiv) and [Pd] catalyst in THF.

^bDetermined by ¹H NMR integration relative to the internal standard. Isolated yield shown in parenthesis.

With optimized conditions in hand (Table 1, entry 10), we examined the amine scope for this protocol using naphthalene (5) and benzene (6, Table 2). Aside from methylbenzylamine (7a), other acyclic secondary amines proved to be viable nucleophiles, as exemplified with dimethylamine (7b) and diethylamine (7c), which gave products with similar yields. Moreover, cyclic secondary amines, such as pyrrolidine, piperidine, morpholine, and N-methylpiperazine, were good substrates for this transformation as well (7d–7h). In addition to naphthalene (5), benzene (6) also showed the desired reactivity, delivering products 8a–8d with a representative set of linear (8a and 8b) and cyclic (8c and 8d) secondary amines. Next, we explored the dearomative diamination process with primary amines as substrates and observed significant erosion in yields using Pd(PPh₃)₄ as the catalyst. Gratifyingly, after performing an additional screen, we found that changing the catalyst to Pd₂(dba)₃/dppf (2.5/6.0 mol %) greatly improved efficiency for these substrates. Thus, the reaction of naphthalene (5) with a range of aliphatic amines, such as linear propyl-, pentyl-, and benzylamine (7i–7k), or branched isopropyl-, cyclohexyl-, and tert-butylamine (7l–7n), all gave products in good yields. Notably, this dearomative difunctionalization is mild enough to tolerate a variety of functionality as demonstrated with products derived from amines incorporating alkene (7o), silyl-protected alcohol (7p), and ester groups (7h and 7q). We also tested the scalability of this transformation by conducting dearomative difunctionalization of naphthalene with propylamine on a gram scale; accordingly, we obtained 7i in 74% yield on an 8.8 mmol scale. Finally, benzene (6) reacted successfully with primary amines, albeit slightly lower yields of products 8e–8h were obtained compared to naphthalene. Throughout these experiments, disubstituted products are formed as single diastereo- and constitutional isomers (see Table 2 for representative X-ray structures of 7a, 8d, 7i, and 8f).

Table 2.

Amine Scope of the Dearomative syn-1,4-Diamination of Naphthalene (5) and Benzene (6)^a

^aStandard reaction conditions for naphthalene (5): MTAD (1, 0.5 mmol, 1.0 equiv), naphthalene (5, 1.0 mmol, 2.0 equiv), EtOAc (0.1 M), visible light, −50 °C, 12 h; then addition of amine (1.0 mmol, 2.0 equiv) and [Pd] catalyst in THF, −20 °C, 20 h. Reaction conditions for benzene (6): MTAD (1, 1.0 mmol, 1.0 equiv), benzene (6, 10 mmol, 10 equiv), CH₂Cl₂ (0.2 M), visible light, −78 °C, 12 h; then addition of amine (2.0 mmol, 2.0 equiv) and [Pd] catalyst in THF, −20 °C, 20 h. Reported yields are of isolated products.

We next investigated the scope of arenes using propylamine as an amine source (Table 3). While benzene worked well (Table 2, insets), substituted mononuclear analogs proved to be unproductive substrates for this reaction. On the other hand, polynuclear arenes delivered desired products 10a–10d. In the case of 10b–10e, mixtures of constitutional isomers were observed, resulting from the lack of regioselectivity in opening the nonsymmetrical arene–arenophile cycloadducts.¹⁹ Additionally, polynuclear heteroarenes were also amenable to dearomative syn-1,4-diaminofunctionalization, providing products 10e–10h. Compared to arene-derived products 10a–10d, these heteroarene-based compounds were obtained with noticeably higher selectivities. In all cases, dearomative cycloaddition with polynuclear arenes proceeded in a highly site-selective manner; functionalization was observed only at the terminal, nonsubstituted ring.

Table 3.

Arene Scope of the Dearomative syn-1,4-Diaminationa^a

^aStandard reaction conditions: MTAD (1, 1.0 mmol, 1.0 equiv), arene (9, 2.0 mmol, 2.0 equiv), EtOAc (0.1 M), visible light, −50 °C, 12 h; then addition of nPrNH₂ (2.0 mmol, 2.0 equiv) and [Pd] catalyst (5 mol %) in THF, −50 to 0 °C, 5 h. Reported yields are of isolated products, with ratios of constitutional isomers (in parentheses) determined by 1H NMR of the crude reaction mixtures.

^b[Pd] catalyst in THF, −20 °C, 20 h.

^cCH₂Cl₂ was used instead of EtOAc.

^d10 mol % of [Pd] catalyst was used.

^eCycloaddition was run at 0.05 M concentration.

We then focused on providing an enantioselective variant of this transformation for the arene–arenophile cycloadducts that are amenable to desymmetrization (Table 4). Accordingly, we screened chiral ligands that could enable asymmetric diamination of naphthalene, and observed high enantioselectivities with Pd₂(dba)₃ and (S,S_p)-tBu-Phosferrox (2.5/6.0 mol %). Using this protocol, a representative collection of amine–naphthalene adducts were obtained from secondary (7e and 7f) and primary amines (7i, 7l, and 7m) with selectivities ranging from 97:3 to 99:1 er.

Table 4.

Pd-Catalyzed Enantioselective Dearomative syn-1,4-Diaminationa^a

^aStandard reaction conditions: MTAD (1, 0.5 mmol, 1.0 equiv), naphthalene (5, 1.0 mmol, 2.0 equiv), EtOAc (0.1 M), visible light, −50 °C, 12 h; then addition of amine (1.0 mmol, 2.0 equiv) and Pd₂(dba)₃ (2.5 mol %) and (S,S_p)-tBu-Phosferrox (6.0 mol %) in THF, −20 °C, 20 h. Reported yields are of isolated products.

The dearomative elaboration described herein can serve as an entry point for rapid molecular diversification and structural elaboration of amine-containing drugs (Figure 2). For example, representative product 7i encompasses several handles for further functionalization (Figure 2a). Accordingly, the corresponding unsaturated amines 11 and 12, saturated amine 13, aminoketone 14, and differentially substituted diamine 15 were obtained from 7i in one to three steps.²⁰ We were also interested in probing this dearomative diamination protocol as a tool for diversification of medicinally relevant amines (Figure 2b). Thus, memantine (16), an FDA-approved drug used for the treatment of dementia associated with Alzheimer’s disease, was further elaborated with naphthalene. Using our standard conditions (see Table 2), dearomatized product 7r was obtained in 66% yield. Moreover, in one to three steps, this intermediate was further diversified to alkene 17, saturated ketone 18, and diaminodiol 19, showcasing the diverse functionalization opportunities this chemistry provides.

Figure 2.

(a) Diversification of product 7i. (b) Elaboration of anti-Alzheimer drug memantine (16). Reagents and conditions: (a) Li, NH₃, 60%; (b) (i) H₂, Rh/Al₂O₃ (cat.), 83%; (ii) HCl, 48%; (c) (i) H₂, Rh/Al₂O₃ (cat.), 83%; (ii) Li, NH₃, 71%; (d) (i) H₂, Rh/Al₂O₃ (cat.), 83%; (ii) tBuOCl, 50%; (e) (i) Boc₂O; then NaOMe 79%; (ii) PhCOCH₂Br, K₂CO₃, 81%; (iii) KOH, 64%; (f) Li, NH₃, 64%; (g) H₂, Rh/Al₂O₃ (cat.), 57%; (ii) tBuOCl, 80%; (h) (i) PhCOCH₂Br, K₂CO₃, 71%; (ii) OsO₄ (cat.), NMO, 80%; (iii) KOH, 58%.

In summary, we have reported a dearomative diamination strategy. This process involves visible-light-mediated para-cycloaddition of arenes with an arenophile and subsequent Pd-catalyzed ring-opening of the resulting cycloadducts with amines as nucleophiles. A variety of amines and arenes provided products with exclusive syn-1,4-selectivity, and high enantioselectivity was observed for the desymmetrization of naphthalene. The corresponding dearomatized products offered unique access to functionalized small molecules, as they contained unsaturation and the arenophile motif, which could be used for further manipulations. The synthetic value of this method has also been demonstrated by rapid and selective elaboration of memantine, an anti-Alzheimer drug, into new analogs. Finally, from a practical perspective, it is noteworthy that this dearomatization protocol could be conducted on a gram scale without significant loss of efficiency. Further studies regarding scope and utility, as well as the development of related transformations and applications of this method, are ongoing and will be reported in due course.