Hydroamination of alkenyl N-arylhydrazones mediated by t-BuOK for the synthesis of nitrogen heterocycles

Abstract

The t-BuOK-mediated reactions of γ,δ-alkenyl N-arylhydrazones enabled intramolecular hydroamination with the outer nitrogen, affording tetrahydropyridazine derivatives. DFT calculations demonstrated a clear distinction in the chemical reactivity between hydrazones and analogous oximes in inorganic base-mediated hydroamination.

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Shunsuke Chiba

Shunsuke Chiba earned his Ph.D. in 2006 from the University of Tokyo (Prof. Koichi Narasaka). He was appointed as a research associate at the University of Tokyo in 2005. He began his independent career at Nanyang Technological University (Singapore) as an Assistant Professor in 2007. In 2012, he was promoted to Associate Professor (with tenure) in the same university. His research focus is on methodology development in the area of synthetic organic chemistry.

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As one of the most efficient ways to construct nitrogen-heterocycles,^1,2 intramolecular hydroamination of alkenyl amines and their derivatives has been intensively studied with various metal complexes (alkali metals, transition metals, and f-block elements) as well as Brønsted acids.^3,4 We have recently studied inorganic base-mediated hydroamination of alkenyl oximes and hydrazones for the synthesis of nitrogen-heterocycles.⁵ The reactions of γ,δ-alkenyl oximes mediated by potassium bases such as K₃PO₄ and t-BuOK proceeded in an unprecedented fashion to yield 5-membered ring nitrones, which were formed via nucleophilic amination of inactivated alkenes by the oxime nitrogen (Scheme 1a).^5a Density functional theory (DFT) calculations suggested that the ionic interaction between the potassium cation on the oxime oxygen and the negatively charged alkene moiety stabilizes the transition state. On the other hand, t-BuOK-mediated reactions of γ,δ-unsaturated N-alkylhydrazones led to the construction of pyrrolidine skeletons via hydrazone–hydrazone isomerization with a 1,3-proton shift followed by the nucleophilic hydroamination; in this reaction, modification of the substituents on the hydrazone moiety greatly affected the diastereoselectivity (Scheme 1b).^5b Based on these findings, we wondered whether γ,δ-alkenyl N-arylhydrazones, for which hydrazone–hydrazone isomerization is not possible, undergo cyclization in the same way as the oximes, to form the corresponding 5-membered ring azomethineimines or afford tetrahydropyridazines via 6-exocyclization with the outer nitrogen.^6,7 We herein report the results from our experimental and theoretical studies to address this question.

Scheme 1 Inorganic base-mediated hydroamination of alkenyl oximes and hydrazones.

Our investigation was commenced with the reactions of γ,δ-alkenyl N-phenylhydrazone 1a (Table 1). The reaction with 1 equiv. of t-BuOK⁸ in o-xylene proceeded at 135 °C (entry 1), resulting in the formation of 6-membered ring tetrahydropyridazine 2a in 62% yield via hydroamination of the alkene with the outer nitrogen atom (marked in blue), while the formation of azomethineimine 2a′ was not observed at all. Further optimization of the reaction conditions revealed that addition of Et₃COH as an additive could improve the yield of 2a (entry 2). The reactions with catalytic amounts of t-BuOK were not optimal for this reaction (entries 3 and 4). The reaction in DMF performed well (entry 5), while that in DMSO became sluggish (entry 6). It is noted that the reactions of 1a with t-BuOLi and t-BuONa as well as other potassium bases such as K₃PO₄ and K₂CO₃ gave no hydroamination product 2a.

Table 1 Optimization of reaction conditions^a,b

Entry	t-BuOK (equiv.)	Et3COH (equiv.)	Solvent	Yield of 2a^b (%)
a Unless otherwise noted, the reactions were carried out on the scale of 0.5 mmol of hydrazone 1a in the solvent (5 mL) under an Ar atmosphere. b Isolated yields were recorded. c Recovery yields of 1a based on ^1H NMR.
1	1	0	o-Xylene	62 (23)^c
2	1	3	o-Xylene	84
3	0.2	3	o-Xylene	10 (82)^c
4	0.4	3	o-Xylene	44 (50)^c
5	1	3	DMF	62(11)^c
6	1	3	DMSO	42

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Having observed the distinct reaction outcomes for inorganic-base mediated hydroamination of oximes (Scheme 1a) and N-phenylhydrazone 1a, we performed DFT calculations at the B3LYP/6-311+G(d,p) level using Gaussian 09,^9–11 to gain mechanistic insights. We examined 5-membered (path A) and 6-membered ring formation (path B) pathways. The solvent effect of o-xylene was included in the calculation using the IEFPCM method,¹² and frequency calculation was performed for each optimized geometry, which yielded a zero-point vibrational energy (ZPE) value. Fig. 1a shows the energy profile obtained for the reaction of hydrazone 1a.¹³ The sequence of deprotonation and protonation allows facile E/Z isomerization of the N–N bond through the diazene intermediate 1a′. The relative energy of the transition state for the 6-membered ring formation (TS1a-A-E) is not too high (20.2 kcal mol⁻¹) with respect to 1a-A-Z, consistent with the experimental fact that the reaction of hydrazone 1a yielded 2a. Nevertheless, the organopotassium intermediate 2a-A is higher in energy than the reactant state (1a-A-Z) by 19.1 kcal mol⁻¹, which will render the equilibrium between these two states largely in favor of the reactant state. The reason why the yield of 2a became higher in the presence of Et₃COH is probably because Et₃COH donates a proton to the carbanion 2a-A to facilitate the reaction in the forward direction.¹⁴

Fig. 1 (a) Energy diagrams (in kcal mol⁻¹) for the reaction of the deprotonated hydrazone, determined at the B3LYP(IEFPCM)/6-311+G(d,p) level with ZPE corrections. (b) Variation of energy (in kcal mol⁻¹) with a decreasing N–C bond distance, as obtained from relaxed energy calculations.

The DFT calculations further showed that the reaction of hydrazone 1a favors 6-membered ring formation (path B) over the 5-membered ring one (path A). In fact, a local energy minimum corresponding to a 5-membered ring intermediate did not exist on the potential energy surface (see Fig. 1b, path A). This trend is markedly different from that for the oxime substrate, which favors 5-membered ring formation (Fig. S1†).^5a In contrast to the case of hydrazone, a 6-membered ring intermediate was not obtained for the oxime substrate (Fig. S3†). To identify the reason why hydrazone 1a selectively undergoes 6-membered ring formation, we inspected the highest occupied molecular orbitals (HOMOs). The HOMO of 1a-A-E is a π-type orbital, which extends perpendicularly to the C=N–N plane, while the HOMO-1 is an in-plane lone-pair type orbital (Fig. 2a). The latter orbital will be mainly responsible for the nucleophilic attack on the alkene carbon. The HOMO-1 has large distributions on both of the two nitrogen atoms of the hydrazone moiety, suggesting that these two nitrogen atoms are almost equally reactive. However, 5-membered ring formation causes a significant steric clash between the phenyl groups on the hydrazone and alkenyl moieties. To prevent this steric clash, the C=N–N–Ph moiety undergoes rotation, which disrupts the stabilization gained by conjugation (Fig. 2b, path A). The C–N–N–C torsion angle of this moiety was −138.2° at r = 1.8 Å, indicating a significant loss of planarity. By contrast, the steric clash is much less severe in the 6-membered ring formation, as reflected by the almost unaltered planarity of this moiety at TS1a-A-E (torsion angle = 175.4°, see Fig. 2b, path B). These explain why a 6-membered ring is preferentially formed in the hydroamination of hydrazone 1a.¹⁵

Fig. 2 (a) HOMO and HOMO-1 of 1a-A-E. The values in parentheses are the orbital energy levels in hartrees. (b) Geometries of 1a-A-Z at r = 1.8 Å (left) and TS1a-A-E (right).

Having obtained the optimal reaction conditions for hydroamination of hydrazone 1a (Table 1, entry 2) and an understanding of the reaction mechanism, we next examined the substrate scope using a variety of hydrazones 1 (Scheme 2). The reactions with varying R¹ allowed for the installation of not only aryl/heteroaryl units (for 2b–d) but also a methyl group (for 2e), while maintaining good product yields. We then turned our attention to the substituents on the alkene (R² and R³). The steric effects did not influence the reaction outcome for hydroamination of aryl alkenes (for 2f and 2g). Hydroamination with even an electron-rich aryl alkene (for 2h) proceeded smoothly. The reaction of hydrazone 1i having the trisubstituted E-alkene with Ph as R² and Me as R³ did not retain alkene stereochemistry in the present hydroamination step, affording a 1 : 1 diastereomeric mixture of 2i. This result implies that the present hydroamination proceeds in a stepwise manner via the carbanion intermediate like 2a-A in Fig. 1. The reaction of N-(para-methoxyphenyl)hydrazone 1j gave a good yield of the hydroamination product 2j. Spirocyclic structures could be constructed in moderate to good yields (for 2k and 2l). The reactions of 1m and 1n having α-proton(s) proceeded well to give the corresponding tetrahydropyridazines 2m and 2n in 76% and 81% yields, respectively.

Scheme 2 ^a Unless otherwise noted, the reactions were carried out on the scale of 0.5 mmol of hydrazones 1 in o-xylene (5 mL) under an Ar atmosphere. ^b Isolated yields were recorded. ^c The 2-step yield from ketone (0.5 mmol) via hydrazone formation and hydroamination was noted. See the ESI† for more details. ^d The reaction was conducted in the presence of t-BuOH (10 equiv.) instead of Et₃COH. ^e The reaction was conducted using 0.3 mmol of 2i. ^f The diastereomeric ratio was judged by ¹H NMR analysis of the isolated mixture of 2 and shown in parentheses.

The present hydroamination of hydrazones was applied to the functionalization of the terminal alkene 1o, which gave tetrahydropyridazine 2o and dihydropyrazole 3o in 39% and 8% yields, respectively, along with 21% recovery of 1o (Scheme 3a). Dihydropyrazole 3o was formed presumably via 5-exo cyclization of β,γ-unsaturated hydrazone 1o′, which is generated via alkene isomerization from the terminal to the internal under the present reaction conditions. Indeed, the present hydroamination method enabled us to construct dihydropyrazole 3p in 90% yield via 5-exo hydroaminative cyclization of β,γ-unsaturated hydrazone 1p (Scheme 3b).

Scheme 3 ^a The reactions were carried out on the scale of 0.5 mmol of hydrazones 1 in o-xylene (5 mL) under an Ar atmosphere. ^b Isolated yields were recorded above.

In summary, we have developed t-BuOK-mediated hydroamination of alkenyl N-arylhydrazones mainly for the synthesis of tetrahydropyridazine derivatives. Hydrazones have exhibited a wide spectrum of chemical reactivity owing to their unique chemical structure.¹⁶ In the area of azaheterocycle synthesis, hydrazones have been typically utilized in the Fischer indole synthesis¹⁷ and as a precursor of azomethine imine 1,3-dipoles for [3 + 2]-cycloaddition with dipolarophiles.^18,19 The present work offers a new reaction entry of hydrazones towards azaheterocycle synthesis, which is enabled by a simple operation with t-BuOK.

This work was supported by funding from Nanyang Technological University (NTU) and the Singapore Ministry of Education (Academic Research Fund Tier 2: MOE2012-T2-1-014). H. H. thanks the High Performance Computing Centre of NTU for computer resources.

Notes and references

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13. The stereochemistry of the hydrazone N–N bond does not influence the outcome of the present hydroamination, as E/Z-isomerization of the N–N bond occurs readily under the present reaction conditions.
14. Prior deprotonation of hydrazone 1a is essential for the cyclization reaction, because the reaction of neutral hydrazone 1a has a very high energy barrier (see the ESI, Fig. S2†).
15. On the other hand, the HOMO of the deprotonated oxime is an in-plane orbital (see the ESI, Fig. S4†). The HOMO lobe is highly localized on the nitrogen, especially on the side of new bond formation, which is beneficial for 5-membered ring formation. However, the HOMO lobe on the oxygen atom looks like a pure p-orbital and is nearly perpendicular to the N–O bond. Thus, the oxygen may not be able to interact with the alkene effectively (Fig. S5b†). These characteristics of the HOMO seem to provide a rationale for the observation that the formation of a 5-membered ring is preferred in the oxime case.
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Footnote

† Electronic supplementary information (ESI) available: Experimental details, including procedures, syntheses and characterization of new compounds; ¹H and ¹³C NMR spectra. CCDC 1001827–1001792. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6qo00053c

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