2-(1-Methylhydrazinyl)pyridine as a reductively removable directing group in a cobalt-catalyzed C(sp²)–H bond alkenylation/annulation cascade

Abstract

We describe a new application of 2-(1-methylhydrazinyl)pyridine as a bidentate directing group to directing cobalt-catalyzed C(sp²)–H alkenylation/annulation of the corresponding benzoic hydrazides to form an isoquinoline backbone, via reacting with a terminal or internal alkyne followed by annulation. The reaction shows a broad substrate scope with the products obtained in good to excellent yields and high regioselectivity. Moreover, the directing group can be reductively removed in one step under mild conditions.

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Research on transition metal-catalyzed C–H functionalization has increased significantly over the past decades¹ and emerged as a powerful strategy for efficient and economic synthesis of complex natural products.² The control of the site selectivity is challenging and the use of a directing group has proven to be a common, practical, and powerful strategy. In 2005, Daugulis and coworkers reported a groundbreaking palladium-catalyzed C(sp³)–H arylation using 8-aminoquinoline as a bidentate directing group with excellent regioselectivity.³ It was believed that bidentate auxiliaries could generate stable metallacycles and promote C–H activation. After their pioneering work, 8-aminoquinoline was widespreadly studied and proved to be the most successful and promising bidentate directing group,⁴ which set a stage for the further development of novel approaches toward selective C–H functionalization. Various new bidentate auxiliaries have been disclosed over the past few years,^3,5 but most auxiliaries incorporate a stable C–N linkage that is relatively difficult to remove. Thus, development of novel removable bidentate directing groups remains highly desirable. To the best of our knowledge, the bidentate auxiliaries containing the N–X (X = S and N) linkage seem to be rare,⁶ although it is well known that the N–X linkage can be easily cleaved in a traceless fashion compared to the C–N counterpart. Therefore, it is essential to develop new N-hetero bond-containing directing groups that are both easily available and readily removable.

In general, transition metal-catalyzed C–H activation relies mainly on noble metal (such as Ru,⁷ Rh,⁸ or Pd⁹) catalysts. In spite of their high catalytic activity, these metals are less abundant in nature. So, it would be economically advantageous to achieve catalytic C–H activation using more abundant and lower atomic weight transition metals with comparable efficacy. Recently, cobalt-catalyzed C–H activation has attracted considerable attention in its low valence,¹⁰ cationic,¹¹ or other forms.¹² Because of its high reactivity, low cost, low toxicity, and abundant availability from the natural sources, cobalt was considered as an attractive catalyst for C–H activation.

Based on the considerations mentioned above, we envisioned that 2-(1-methylhydrazinyl)pyridine might be a promising bidentate auxiliary candidate,¹³ since it can be easily obtained from 2-chloropyridine and methylhydrazine at low cost. Also, the N–N linkage can be much more easily cleaved compared to most other bidentate directing groups (Scheme 1). Cobalt-catalyzed C(sp²)–H alkenylation/annulation assisted by a bidentate directing group was pioneered by Daugulis and coworkers,¹⁴ and later flourished by the groups of Zhang,¹⁵ Song,¹⁶ and Ackermann¹⁷ (Scheme 2a and b). Inspired by the previous studies, we initiated our investigations (Scheme 2c) on the reaction of N′-methyl-N′-(pyridin-2-yl)benzohydrazide (1a) with phenylacetylene (2a), using the catalytic system reported by Daugulis.¹⁴ Gratifyingly, the reaction generated the desired product 3aa in moderate yield (Table 1, entry 1), and the structure of 3aa was determined by an X-ray diffraction analysis.¹⁸ Encouraged by the above results, we then screened some other bases for the reaction and found that Na₂CO₃ and K₂CO₃ were both slightly better than NaOPiv (entries 2 and 3). A significant increase of the reaction efficiency was observed when 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) was used as the solvent (entry 4). The yield of 3aa was further increased by the incorporation of tetrabutylammonium iodide (TBAI) as a phase-transfer catalyst into the reaction system (entry 5).¹⁵ In addition, control experiments indicated that the C–H activation step was completely inhibited in the absence of either Co(OAc)₂·4H₂O or Mn(OAc)₃·2H₂O (entries 6 and 7). Nevertheless, the reaction could still proceed to some extent without a base (entry 8).

Scheme 1 Novel bidentate directing group-assisted C–H activation.

Scheme 2 Cobalt-catalyzed C–H activation.

Table 1 Substrate scope studies^a

Entry	Oxidant	Base	Solvent	Yield^b (%)
a Reaction conditions: 1a (0.25 mmol), 2a (2.0 equiv.), Co(OAc)2·4H2O (20 mol%), air, 100 °C, 24 h. b Isolated yield. c TBAI (2.0 equiv.) was added. d No cobalt was added.
1	Mn(OAc)3·2H2O	NaOPiv	TFE	51
2	Mn(OAc)3·2H2O	Na2CO3	TFE	61
3	Mn(OAc)3·2H2O	K2CO3	TFE	61
4	Mn(OAc)3·2H2O	Na2CO3	HFIP	84
5	Mn(OAc) 3 ·2H 2 O	Na 2 CO 3	HFIP	90
6^c^,^d	Mn(OAc)3·2H2O	Na2CO3	HFIP	N.D.
7^c	—	Na2CO3	HFIP	N.D.
8^c	Mn(OAc)3·2H2O	—	HFIP	44

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The scope for the alkynes was next investigated under the optimal reaction conditions obtained above (see Table 1, entry 5). In general, both electron-rich and electron-deficient alkynes were compatible with the reaction (Table 2, 3aa–3ak). For example, phenylacetylene and 1-ethynyl-4-pentylbenzene produced nearly equivalent yields (3aa and 3af). Phenylacetylenes with a substituent on the benzene ring such as fluoro (3ag and 3ah), chloro (3ai), bromo (3aj), and methoxy (3ak) groups were well tolerated, providing ample opportunities for further derivatization of the products. 2-Ethynylthiophene (3al) and ethyl propiolate (3am) were also suitable for this reaction. Furthermore, internal alkynes such as diphenylacetylene and its derivatives did not appear to influence the reactions, and gave the products in moderate to good yields (3an¹⁹ and 3ao). In the cases of trimethylsilylacetylene (3ap) and cyclopropyl acetylene (3aq), the corresponding cyclization products were formed in high yields, yet with relatively low regioselectivities.

Table 2 The scope for the alkynes^a

a Reaction conditions: 1 (0.25 mmol), 2n (2.0 equiv.), Co(OAc)₂·4H₂O (20 mol%), Na₂CO₃ (2.0 equiv.), Mn(OAc)₃·2H₂O (2.0 equiv.), TBAI (2.0 equiv.), HFIP (2 mL), 100 °C, air, 24 h. b The regioisomeric ratio was determined based on ¹H NMR integrals.

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Subsequently, a wide range of hydrazides were explored in the cobalt-catalyzed annulation with alkyne 2n (Table 3). Benzoic hydrazides containing either an electron-donating or electron-withdrawing group (e.g., methyl, methoxy, fluoro, chloro, bromo, or iodo group, in the para-position) on the benzene ring (3bn–3gn) worked well in this reaction. Moreover, the hydrazide with a para trifluoromethyl group furnished the product in 72% yield (3hn), indicating that the reaction might not be very sensitive to the electronic effect. A single product was generated in an excellent yield of 90% with the meta-methyl-substituted benzoic hydrazide 3in used as the substrate, therefore the current reaction might have a strong steric effect. Indeed, ortho-substituted benzoic hydrazides with either an electron-donating or an electron-withdrawing group gave the corresponding annulation products in only moderate yields (3jn, 3kn, and 3ln). Moreover, for the hydrazide with a heteroaromatic moiety 1m, no desired product (3mn) was formed at all, even at an elevated reaction temperature.

Table 3 The scope for the hydrazides^a

a Reaction conditions: 1 (0.25 mmol), 2n (2.0 equiv.), Co(OAc)₂·4H₂O (20 mol%), Na₂CO₃ (2.0 equiv.), Mn(OAc)₃·2H₂O (2.0 equiv.), TBAI (2.0 equiv.), HFIP (2 mL), 100 °C, air, 24 h. b The reaction was performed for 16 h.

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One of the significant merits of the current strategy lies in the reductive removal of the methylaminopyridine moiety (originated from the ligand) under mild conditions. For instance, upon the N–N bond cleavage through treatment with SmI₂ at 0 °C to room temperature overnight, compounds 3an, 3en, and 3fn were transformed smoothly into amides 5–7 in 88–94% yields (Scheme 3).^20,21

Scheme 3 Reductive removal of the directing group.

In order to gain further insight into the nature of the present reaction, the following experiments were performed to probe the reaction mechanism (Scheme 4). An intermolecular kinetic isotope effect (KIE) experiment was carried out between hydrazide 1a and isotopically labelled substrate [D₅]-1a under standard reaction conditions (Scheme 4a), resulting in a K value of approximately 1.5, suggesting that the first step (for the formation of A) in the catalytic cycle was only slightly affected by the H/D isotope. Furthermore, no H/D exchange could be detected in both the reaction of isotopically labelled substrate [D₅]-1a with 2n and that of 1a with 2n with CD₃OD added as a co-solvent, indicating presumable irreversibility of the C–H cobaltation step (Scheme 4b).

Scheme 4 Preliminary mechanistic studies.

Based upon our preliminary mechanistic studies and the relevant literature reports,^17,22 we proposed a mechanism for the cascade reaction sequence (Scheme 5). First, Co(II) is oxidized to Co(III) by Mn(OAc)₃·2H₂O. The chelation of Co(III) to hydrazide 1 followed by the subsequent C–H activation produces intermediate A. Alkyne 2 is then coordinated to the Co(III) center within intermediate A to provide intermediate B. Coordinative insertion of the carbon–carbon triple bond into the C–Co bond of intermediate B results in the seven-membered intermediate C, and the reductive elimination of which gives the desired product 3 as well as the low-valent Co(I). The active Co(III) species was regenerated through the oxidation of Co(I) with Mn(OAc)₃·2H₂O and O₂, and the regenerated Co(III) species enters the next catalytic cycle.

Scheme 5 Proposed reaction mechanism.

In conclusion, we have developed an efficient cobalt-catalyzed C(sp²)–H bond alkenylation/annulation cascade reaction of benzoic hydrazides with various terminal or internal alkynes via a novel 2-(1-methylhydrazinyl)pyridine-assisted C–H activation, providing a new rapid access to a series of isoquinoline derivatives. Moreover, the methylaminopyridine moiety originated from the ligand can be reductively removed under mild conditions. Further applications of 2-(1-methylhydrazinyl)pyridine as a bidentate directing group in other related types of C–H functionalization and detailed understanding of the mechanisms are currently being investigated in our laboratory.

We thank the NSFC (21732001, 21672017, 21472072, and 21290183), the Shenzhen Science and Technology Innovation Committee (JCYJ20150529153646078 and JSGG20160229150510483), the Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT: IRT_15R28), and the “111” Program of MOE for financial support.

Conflicts of interest

There are no conflicts to declare.

Notes and references

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18. The structure of compound 3aa was confirmed by X-ray crystallography, CCDC 1547832†.
19. The structure of compound 3an was confirmed by X-ray crystallography, CCDC 1548078†.
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21. Application of a lower amount of SmI₂ resulted in a much lower yield of the product although the unreacted starting material could be recovered.
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Footnote

† Electronic supplementary information (ESI) available. CCDC 1547832 and 1548078. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c7cc08533h

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