Cross-Coupling of Amines via Photocatalytic Denitrogenation of In Situ-Generated Diazenes

Abstract

A method for C(sp³)–C(sp³) cross-coupling of amines is described. Primary amines are converted to 1,2-dialkyldiazenes by treatment with O-nosylhydroxylamines in the presence of atmospheric oxygen. Denitrogenation of the diazenes with an iridium photocatalyst then forges the C–C bond. The substrate scope accommodates a broad latitude of functionality, including heteroaromatics and unprotected alcohols and acids.

Graphical Abstract

Cross-coupling reactions are highly valued for their ability to construct complex carbon frameworks from simple precursors.¹ While conventional cross-couplings utilize coupling partners such as organohalides, organometallics, or boronic acids, recent years have witnessed major efforts to extend the range of functional groups that can be engaged.² Of particular interest is the cross-coupling of “native” functionalities, such as alcohols³ and carboxylic acids,⁴ due to their prevalence in natural and synthetic chemical feedstocks. In contrast, amines, which are also broadly available,⁵ have less commonly been used as cross-coupling partners. This relative paucity is a reflection of the basicity of the amino nitrogen, which tends to complicate transition metal-based reactions, and the strength of the C–N bond.⁶ Nevertheless, several strategies have been developed to cross-couple amines, most notably through their conversion to Katritzky-type pyridinium salts⁷ or to redox-active imines,⁸ which enables the requisite scission of the C–N bond. While these advancements have enabled impressive transformations of amines, C(sp³)–C(sp³) coupling reactions have been limited to radical additions to alkenes,⁹ coupling with alkyl metal reagents¹⁰ and radical couplings with specialized substrates.¹¹ Thus, there remains a strong interest in the development of amine cross-coupling reactions that are simple, versatile, and broadly tolerant of various functional groups for the direct generation of new C(sp³)–C(sp³) coupled products. Here, we report such a method involving the photocatalytic denitrogenation of in situ-generated diazenes.¹²

It is well known that diazenes can be induced to expel molecular nitrogen, leaving behind carbon-centered radicals that can combine to form C–C bonds.¹³ Indeed, this reactivity has been employed in wide-ranging applications, including for the total synthesis of highly complex natural products.¹⁴ Unfortunately, the current state of the art for this chemistry suffers from several limitations. First, the synthesis of dialkyldiazenes, particularly those with α-C–H bonds, can be challenging because they are prone to isomerize to hydrazones¹⁵ which are inactive for denitrogenation. Second, the denitrogenation step often requires elevated temperatures¹⁶ or UV radiation,¹⁷ which promotes side reactions and limits functional group compatibility. Nevertheless, because the loss of molecular nitrogen provides a powerful driving force that can be leveraged to construct very challenging bond connections, we reasoned that solving the above-mentioned challenges would result in a powerful C–C bond-forming method.

In regard to the denitrogenation problem, we recently reported the electrophotocatalytic decomposition of diazenes to form olefin products (e.g. 2 → 1, Figure 1), using a trisaminocyclopropenium catalyst 4 that enabled the formation of distonic radical cation intermediates.¹⁸ As part of that work, we demonstrated that iridium photocatalyst 5 resulted instead in the generation of a diradical intermediate, leading to exclusive C–C bond formation, i.e. 2 → 3. This latter denitrogenation is believed to occur via energy transfer from the photoexcited iridium complex to the diazene group,¹⁹ a process that has been employed to great effect for the related decomposition of diazirines to form carbenes.²⁰ In brief, the photocatalyst [Ir] can absorb a photon to access the singlet excited state ¹[Ir]*, which can undergo intersystem crossing to the triplet state ³[Ir]* (see Figure 1). Energy transfer from this triplet state to the diazene can then generate the triplet excited state of the diazene. Expulsion of nitrogen from this triplet excited state gives rise to two radical fragments that can recombine to form a new C–C bond. We recognized that this photocatalytic denitrogenation of 1,2-dialkyldiazenes²¹ could enable an attractive means to cross-couple amines if 1) the process was generally applicable to acyclic diazenes, and 2) a simple synthesis of dialkydiazenes could be developed.

Figure 1.

Cross-coupling of amines via photocatalytic denitrogenation of in situ-generated diazenes.

In regard to the second question, although several methods to prepare dialkyldiazenes are known, they tend to be inefficient,²² and in our hands proved unserviceable for the development of a useful cross-coupling procedure. We envisioned making use of the facile autooxidation of hydrazines²³ as a way to prepare diazenes under mild conditions; our goal thus became to convert a primary amine substrate to a hydrazine intermediate. While it is known that treatment of an amine with an N-chloroamine can forge the requisite N–N bond to form diaziridines,²⁴ N-chloroamines are problematic and did not suit our purposes. Inspired by the diaziridine work and limited examples utilizing tosyl-substituted hydroxylamines,²⁵ we found that reaction with O-nosylhydroxyamines (ONHAs) provided the desired efficiency.

The optimized amine cross-couping conditions we identified involved treatment of a primary amine substrate, such as leelamine, with one equivalent of the isopropyl ONHA•TFA²⁶ salt 6 and 2,6-lutidine in MeCN at room temperature with exposure to air (Table 1). After 12 h, 2 mol% [Ir(dFCF₃ppy)₂(dtbbpy)]PF₆ was added, and the mixture was irradiated by blue LEDs for 24 h. This procedure resulted in an 85% isolated yield of the cross-coupled product 7.²⁷ In addition to this example, products derived from t-Bu glycinate 8 and leucine p-nitroanilide 9 were generated in high yields. Reactions to form products 7 and 8 were also conducted on a preparative scale (1 mmol) with reasonable yields. Meanwhile, we found that unprotected 1,2-aminoalcohols were viable substrates, with aminoindanol furnishing 10 and threonine benzyl ester giving rise to 11, both as single diastereomers. In the case of 10, both cis and trans aminoindanol substrates led to the same trans product. Unprotected amino acids could also be directly coupled, as with products 12-14 derived from asparagine, methionine, and methyldopa respectively. Peptide starting materials aspartame and lisinopril were converted to adducts 15 and 16 in good and modest yields, respectively. The benzazapinone derivative 17 was prepared in 76% yield, and reaction of aminoethyl biotinamide led to 18 in 75% yield.

Table 1.

Scope of photocatalytic cross-coupling of amines with N-isopropyl-O-nosylhydroxylamine^a

^aSee SI for detailed procedures. Reaction Conditions: Amine (1.0 equiv), 6 (1.0 equiv), 2,6-lutidine (2.0 equiv) under ambient air in dry MeCN at room temperature for 12 h, followed by addition of 5 (2 mol%) and irradiation with blue LEDs under N₂ at room temperature for 24 h. Yields determined on purified products. Diastereomeric ratios (dr) determined by 1H NMR spectroscopy.

^bEnantiopure starting materials were used. Products were obtained in racemic form.

^c(1R,2R)-1-aminoindan-2-ol used as substrate. The (1S,2R) substrate furnished the same product diastereomer. Ns = 4-nitrobenzenesulfonyl.

To further explore the applicability of this reaction to complex molecular settings, we examined the cross-coupling of several amine-containing drug molecules. For example, the reactions of fingolimod, oseltamivir, saxagliptin, dehydroamlopidine, sitagliptin, amoxicillin, and linagliptin to furnish adducts 19-25 in good yields highlight the compatibility of this procedure with a range of functionality and complex architectures. Due to the nature of the radical intermediates, stereoselectivity for these reactions relies exclusively on substrate control. Thus, while 20 was formed as a single diastereomer; 21 and 24, derived from substrates with more isolated amino groups, were generated as mixtures of diastereomers.

Next, we examined the scope of the ONHA component, using threonine benzyl ester 26 as the amine coupling partner (Table 2). Carbocycles of various sizes could be engaged to furnish adducts 27-29 with complete diastereoselectivity for the trans product. We also found that products incorporating tetrahydropyran 30 and piperidine 31 rings could be formed in good yields and as single stereoisomers. When non-α-branched ONHA partners were employed, products 32-34 were obtained, albeit as 1:1 mixtures of diastereomers. In the case of product 35, some measure of stereocontrol was exerted by the existing stereocenter on the ONHA coupling partner.

Table 2.

Scope studies for the ONHA coupling partner.^a

^aSee SI for detailed procedures. Reaction Conditions: 26 (1.0 equiv), ONHA (1.0 equiv), 2,6-lutidine (2.0 equiv) under ambient air in MeCN at room temperature for 12 h, followed by addition of 5 (2 mol%) and irradiation with blue LEDs under N₂ at room temperature for 24 h. Yields determined on purified products. Diastereomeric ratios (dr) determined by ¹H NMR spectroscopy.

^bDiastereomeric ratio refers to the α and β stereocenters. Racemic ONHA was used, so all diastereomers were obtained.

Under the assumption that the hydrazine formation step proceeds by nucleophilic attack of the amine on the nitrogen of the ONHA, we anticipated that selective cross-coupling of only one amino group of a diamine substrate based on steric differences might be possible. Indeed, treatment of lysine (36) with one equivalent of ONHA 6 under the standard conditions led to the selective formation of 37 in 68% yield (Figure 2, eq 1). No products derived from reaction of the α-amino group were detected. Finally, we examined the applicability of this amine cross-coupling to forge C–C bonds in the context of a highly complex natural product, namely the antibiotic natamycin (38, Figure 2, eq 2). This macrocyclic compound bears a dense array of potentially sensitive functionality, including multiple hydroxyl groups, an allylic epoxide, a carboxylic acid, and a conjugated tetraene, in addition to the aminoglycan appendage. Even within this formidable setting, this coupling method enabled the formation of isopropyl derivative 39 in 48% yield as a single diastereomer, highlighting the potential for late-stage editing of complex molecules.

Figure 2.

Selective cross-coupling of lysine (eq. 1) and cross-coupling of natamycin (eq. 2).

In summary, we have developed a new method to convert primary amines to C(sp³)–C(sp³) cross-coupled products by employing a simple yet effective 1,2-dialkyldiazene synthesis followed by the use of visible light photocatalysis to trigger their in situ denitrogenation. Because of the mild nature of these conditions, a wide range of functional groups were found to be compatible, including unprotected alcohols, carboxylic acids, and even other amino groups. This work thus expands the ability to utilize widely available amines as building blocks for the construction of complex carbon frameworks.