Dirhodium(II)-Catalyzed Synthesis of N-(Arylsulfonyl)hydrazines by N–H Amination of Aliphatic Amines

Key words

amine - hydrazine - N–N bond - Rh(II) catalyst - nitrene

The nitrogen–nitrogen (N–N) bond is a privileged structural motif in natural products.[1] Among over 200 natural products containing the motif, α-hydrazino acid derivatives are of particular interest because they exhibit a diverse array of biological activities including antibacterial, anti-HCV, and immunosuppressant properties (Figure [1]). α-Hydrazino acids are also prevalent in pharmaceuticals, for example, as core structures of carbidopa and cilazapril. Furthermore, their incorporation into peptides has been investigated to enhance the proteolytic stability or to control conformation.[2]

Figure 1 Natural products and pharmaceuticals containing N–N bond

Despite their importance, the number of methods for intermolecular N–N bond formation are still limited.[3] [4] [5] In addition to classical methods including N-nitrosation, diazotization, and azo coupling of amines followed by reduction, electrophilic N-amination of amines with oxaziridine reagents is widely adopted for the synthesis of hydrazine derivatives.[2] [4] Recently, some research groups have developed oxidative N–N bond formation between two distinct amines or azoles using a Cu catalyst or iodine-based oxidant as well as electrochemical oxidation.[5] However, nucleophilic and oxidation-sensitive amines are likely to cause various side reactions including dimerization via N–N, C–C, and C–N bond formation, and therefore, the combination of substrates is rather limited.

Nevertheless, electrophilic metal–nitrene species generated from metal catalysts and various nitrene precursors are capable of catalytic N–N bond formation with nitrogen-containing heteroaromatics, tertiary amines, or (sulfon)amides to form zwitterionic aminimides (N⁺–N^–).[6] [7] [8] [9] However, reactions with primary or secondary amines are underexplored due to the propensity of the highly nucleophilic substrates to poison the catalysts by strong coordination to the metal center.[10,11] Recently, we reported the synthesis of N-aryl-N′-tosyldiazenes from primary aromatic amines via N–H amination with Rh(II)–nitrene followed by oxidation (Scheme [1a]).[12] To the best of our knowledge, this is the first example of N–H amination using metal–nitrene species. However, the N–H amination of more nucleophilic aliphatic amines remains a major challenge. Herein, we report the N–H amination of α-amino acid derivatives 1 or other aliphatic amines 2 using Rh(II)–nitrene to provide N-(arylsulfonyl)hydrazines 3 or 4 (Scheme [1b]).

Scheme 1 (a) Rh(II)-catalyzed synthesis of N-aryl-N′-tosyldiazenes from aromatic primary amines. (b) Rh(II)-catalyzed N–H amination of aliphatic amines; esp = α,α,α,α-tetramethyl-1,3-benzenedipropanoate, Ts = tosyl, Mes = 2,4,6-trimethylphenyl.

Initially, we performed the reactions of various N-alkyl-α-amino acid esters under previously reported conditions using Rh₂(HNCOCF₃)₄ (4 mol%) and (tosylimino)-2,4,6-trimethylphenyliodinane (TsN=IMes, 5a) in CH₂Cl₂ (0.025 M),[12] and found that 1-aminocyclopropanecarboxylate 1a provided the desired α-hydrazino acid 3aa in 51% yield (Table [1], entry 1).[13] The performance of iminoiodinanes 5b–d bearing various arylsulfonyl groups on the nitrogen atom was also investigated (entries 2–4). Compared with TsN=IMes 5a (entry 1), the use of pNsN=IMes 5b diminished the product yield (entry 2). In contrast, introduction of the electron-donating methoxy group into the arylsulfonyl moiety significantly improved the product yield (entry 3), and product 3ad was obtained in 88% yield by exploiting 3,4-(MeO)₂C₆H₃SO₂N=IMes 5d (entry 4). With the use of 5d, high product yields were maintained with 2 mol% loading of the catalyst (entry 5), and commercially available Rh₂(esp)₂ provided virtually the same result as Rh₂(HNCOCF₃)₄ (entry 6). Similar to our previous work, increasing the concentration of 1a to 0.1 M led to a noticeable drop in the product yields (entry 7).[14] The solvent survey revealed that the use of CF₃C₆H₅ instead of CH₂Cl₂ further improved the yield of 3ad to 94% (entries 8–11). The reaction performed on 1 mmol scale led to only a slight decrease in the product yield.[15]

Table 1 Optimization of Reaction Conditions for N–H Amination of 1-Aminocyclopropanecarboxylate 1a ^a

Entry	Rh(II) catalyst (loading mol%)	Iminoiodinane	Solvent	Yield (%)b
1	Rh2(HNCOCF3)4 (4)	5a	CH2Cl2	3aa 51
2	Rh2(HNCOCF3)4 (4)	5b	CH2Cl2	3ab 30
3	Rh2(HNCOCF3)4 (4)	5c	CH2Cl2	3ac 84
4	Rh2(HNCOCF3)4 (4)	5d	CH2Cl2	3ad 88
5	Rh2(HNCOCF3)4 (2)	5d	CH2Cl2	3ad 92
6	Rh2(esp)2 (2)	5d	CH2Cl2	3ad 89
7	Rh2(esp)2 (2)	5d	CH2Cl2 c	3ad 71
8	Rh2(esp)2 (2)	5d	MeCN	3ad 23
9	Rh2(esp)2 (2)	5d	Et2O	3ad 67
10	Rh2(esp)2 (2)	5d	toluene	3ad 88
11	Rh2(esp)2 (2)	5d	CF3C6H5	3ad 94 (81)d

^a Reaction conditions: 1a (0.10 mmol), Rh(II) catalyst (2–4 mol%), iminoiodinane (0.20 mmol), and MS 4 Å (powder, 40 mg) in the indicated solvent (4.0 mL).

^b Isolated yields.

^c Concentration: 0.1 M.

^d Yield in parenthesis refers to the yield obtained in 1 mmol scale; Ts = tosyl, pNs = p-nosyl, Mbs = 4-methoxyphenylsulfonyl.

With the optimized conditions at hand, we then investigated the influence of the substituent on the amino group (Table [2]). The introduction of either the electron-donating or electron-withdrawing groups into the 2- or 4-position of the benzyl group had little impact on the product yield (entries 1–4). In addition to the N-benzyl substrates, N-allyl substrate 1f uneventfully furnished product 3f (entry 5). The bulky N-isopropyl group led to a significant decrease in the product yield (entry 6). Primary amine 1h also resulted in hydrazine 3h as the sole product in 47% yield (entry 7). In contrast to aromatic amines, the formation of diazene 6 by in situ oxidation for 3h was not observed.[12]

Table 2 N–H Amination of N-Alkyl-1-aminocyclopropanecarboxylates 1b–h

Entry	R	Yield (%)a
1	4-MeOC6H4CH2	3b 90
2	4-O2NC6H4CH2	3c 87
3	4-BrC6H4CH2	3d 95
4	2-BrC6H4CH2	3e 85
5	allyl	3f 86
6	i-Pr	3g 59
7	H	3h 47b

^a Isolated yield.

^b Diazene 6 was not obtained.

Cyclic α-amino acid derivatives 1i and 1j bearing cyclobutene and cyclopentane rings underwent N–H amination as well as 1-aminocyclopropanecarboxylates, and 3i and 3j were obtained in 86% and 85% yields, respectively (Scheme [2]). A high yield was maintained with acyclic substrate 1k. Notably, common α-amino acid derivatives, such as alanine 1l, tyrosine 1m, and glycine 1n, were also suitable substrates for this transformation, and α-hydrazino acids 3l–n were obtained in 71–79% yields. In contrast, proline methyl ester (1o) failed to give the desired product 3o.

Scheme 2 N–H Amination of amino acid derivatives 1i–o; TBS = tert-butyldimethylsilyl

The reactions of amines other than α-amino acids were also examined (Scheme [3]). Unfortunately, dibenzylamine (2a) did not provide the desired N–H insertion product 4a. However, the introduction of one or two methyl groups into the α-position of 2a significantly improved the outcomes, and 4b and 4c were obtained in 54% and 58% yields, respectively. It was speculated that this noticeable difference between 2a and 2b,c was due to catalyst poisoning by the highly nucleophilic 2a.[11]

Scheme 3 N–H Amination of aliphatic amines 2a–c

To validate this hypothesis, the N–H amination of 1a in the presence of 2a was performed (Table [3]). The addition of only 0.2 equiv of 2a led to a decrease in the yield of 3ad from 94% (Table [1], entry 11) to 36%, along with a 30% recovery of the starting 1a. Furthermore, the quantitative amount of 2a completely inhibited the reaction of 1a. Conversely, with 20 mol% of Rh₂(esp)₂, the N–H amination of 1a proceeded even in the presence of a quantitative amount of 2a. These results clearly indicate catalyst poisoning by 2a. A plausible reaction mechanism is illustrated in Scheme [4]. With amino acid derivatives 1 or bulky amines 2b,c, Rh(II)–nitrene species generated from Rh₂(esp)₂ and iminoiodinane 5d undergo nucleophilic addition of the substrates to form N–N bonds. Proton transfer from intermediate I furnishes N–H amination products 3 or 4. Meanwhile, 2a interferes with the generation of Rh(II)–nitrene through the formation of an inactive complex by coordination with Rh₂(esp)₂.

Table 3 N–H Amination of 1a in the Presence of Dibenzylamine (2a)

Entry	2a (equiv)	Rh2(esp)2 (mol%)	Recovered 1a (%)a	Yield of 3ad (%)a
1	0.2	2	30	36
2	1	2	81	ND
3	1	20	31	47

^a Isolated yield.

Scheme 4 Plausible reaction mechanism

In summary, we developed a Rh(II)-catalyzed N–N bond-forming reaction of amino acid derivatives or aliphatic amines to provide hydrazine derivatives through the combined use of Rh₂(esp)₂ and iminoiodinane bearing (3,4-dimethoxyphenyl)sulfonyl group on the nitrogen atom. This is the first report of N–H amination of aliphatic amines with metal–nitrene species. Further studies on the influence of the arylsulfonyl group on the reactivity of Rh(II)–nitrene and the removal of (3,4-dimethoxyphenyl)sulfonyl group are currently in progress.

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It is reported that aminimides formed through the reactions of bicyclic aminals or (sulfon)amides and Rh(II)–nitrene underwent rearrangement to form formal C–N or S–N bond insertion products:
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We previously reported ortho C–H amination of tertiary aromatic amines with Rh(II)–nitrene and presumed that the regioselectivity was due to the interaction between amino group and nitrogen atom of Rh(II)-nitrene:
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An example of hydrazine formation from N-allylaniline is also reported in this study:
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• 13 N-Benzyl-1-aminocyclopropanecarboxylate provided a similar result to 1a. We choose 1a as the substrate because purification of the N–H amination product 3ad was easier than that obtained from the N-benzyl substrate.
• 14 In our previous work, the reaction at higher concentration (0.1 M) led to the formation of azo compounds by dimerization of primary aromatic amines, see ref. 12a.
• 15 Typical Experimental Procedure 3,4-(MeO)₂C₆H₃SO₂N=IMes (5d, 554 mg, 1.20 mmol) was added to a stirred mixture of 1a (233 mg, 1.00 mmol), Rh₂(esp)₂ (15.2 mg, 2.00·10^–2 mmol, 2 mol%), and MS 4 Å (powder, 400 mg) in CF₃C₆H₅ (40 mL) at 0 °C under Ar atmosphere. After stirring at room temperature for 1 h, the whole mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo to furnish the crude product, which was purified by column chromatography (silica gel, 1:1 n-hexane/AcOEt) to give 3ad (364 mg, 81%) as orange oil. IR (KBr): ν = 3279, 2933, 1722, 1511, 1165, 1029 cm^–1. ¹H NMR (400 MHz, CD₃CN, 60 °C): δ = 0.90 (br d, 2 H, c-propane), 1.05 (t, J = 7.2 Hz, 3 H, CH₂CH ₃), 1.25 (br s, 2 H, c-propane), 2.21 (s, 3 H, ArCH₃), 3.66 (s, 3 H, OCH₃), 3.69 (s, 3 H, OCH₃), 3.90 (q, J = 7.2 Hz, 2 H, CH ₂CH₃), 4.41 (s, 2 H, ArCH₂), 6.60 (dd, J = 8.4, 2.6 Hz, 1 H, ArH), 6.62 (d, J = 2.6 Hz, 1 H, ArH), 6.77 (d, J = 8.4 Hz, 1 H, ArH), 7.02 (d, J = 8.0 Hz, 2 H, ArH), 7.09–7.11 (m, 3 H, NH and ArH). ¹³C NMR (100 MHz, CD₃CN, 60 °C): δ = 14.6 (CH₃), 20.1 (CH₂), 21.3 (CH₃), 43.6 (C), 54.8 (CH₂), 56.9 (CH₃), 57.2 (CH₃), 62.5 (CH₂), 109.9 (CH), 113.9 (CH), 116.8 (CH), 130.1 (CH), 130.5 (CH) 131.9 (C), 135.2 (C), 138.8 (C), 148.8 (C), 151.0 (C), 174.0 (C=O). HRMS (EI): m/z calcd for C₂₂H₂₈N₂O₆S [M]⁺: 448.1668; found: 448.1666.