Cp*Co(III)-catalyzed, N–N bond-based redox-neutral synthesis of isoquinolines

Abstract

We report herein a redox-neutral Cp*Co(III)-catalyzed cyclization of acetophenone N-Boc hydrazones with alkynes for streamlined synthesis of isoquinolines, accomplished via formation of a C–C and a C–N bond along with N–N bond cleavage. Moreover, this rapid approach can be completed in 30 min with yields up to 85%.

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The wealth of isoquinoline skeletons in biologically and pharmacologically¹ active molecules has provided a driving force for chemists to develop increasingly efficient methods towards their preparation. Traditional routes, which are demonstrated well by the Bischler–Napieralski reaction,² the Pomeranz–Fritsch reaction³ and the Pictet–Gams reaction,⁴ typically need highly active substrates and harsh reaction conditions. Thus, the development of efficient transformations that exhibit mild conditions and good functional group tolerance is highly desirable. Metal-catalyzed cyclization reactions have been developed to permit mild and efficient syntheses of heterocycles,⁵ including isoquinolines. Initially, most approaches require the use of stoichiometric or superstoichiometric amounts of external oxidants, especially metal salts, to sustain the catalytic turnover, which indisputably results in lower atom efficiency by producing undesired waste byproducts and off-cycle side reactions.⁶ Since chemists were aware of its shortcomings, a new strategy employing internal oxidizing directing groups to regenerate the catalyst was developed. Shortly afterward, this “external-oxidant-free” strategy has created a renaissance for the streamlined synthesis of isoquinolines via Pd,⁷ Ru⁸ and Rh-catalyzed⁹ C–H bond activation. In these internal oxidant protocols, the N–O^7,8,10 and N–N bonds¹¹ have been recruited as a critical handle for both C–N cyclization and catalyst turnover (Scheme 1a). While these methods are effective, their synthetic application may be compromised by the relatively high cost and low abundance of these noble metals.

Scheme 1 Metal-catalyzed redox-neutral synthesis of isoquinolines.

In light of the economic practicality of chemistry, the focus has shifted in recent years to the use of inexpensive and accessible base metal catalysts in lieu of the precious but often used noble transition metals for C–H activation processes. Undoubtedly, great progress has been accomplished with versatile cobalt catalysts which were reported by Kanai/Matsunaga,¹² Sundararaju,¹³ Ellman,¹⁴ Glorius,¹⁵ Ackermann,¹⁶ Chang,¹⁷ and others.¹⁸ For isoquinolines synthesis, however, Cp*Co(III) catalysis has only showcased N–O bond cleavage¹⁹ for oxidative-directing groups to date (Scheme 1b). Although Cp*Co(III)-catalyzed N–N bond cleavage type reactions are reported in indole synthesis,²⁰ isoquinoline synthesis has not been studied. To broaden the area of application for Cp*Co(III)-catalyzed isoquinoline synthesis, we focus on the exploration of new oxidizing motifs as potential directing groups. Here, we make the first report of a redox-neutral Cp*Co(III)-catalyzed synthetic approach for the direct synthesis of isoquinolines based on an N–N bond cleavage (Scheme 1c).

At the outset of our studies, we tested various reaction conditions for isoquinoline synthesis with acetophenone N-Boc hydrazone 1a and diphenylacetylene 2a (Table 1 and ESI Tables 1 and 2†). Preliminary experiments highlighted [Cp*Co(CO)I₂]/AgOTf to be the catalyst system of choice and indicated that HFIP was the most suitable among a variety of solvents (Table SI-1†). For an additive, while acetates such as KOAc gave an unsatisfactory result (entry 1), acids proved to be superior, with HOAc being optimal (entries 2 and 3). The synthesis of product 3a occurred in the absence of silver(I) salts (entry 4), but was more effective when employing both Cp*Co(III) species and AgSbF₆ (entries 5–9). Further systematic optimization with respect to the amount of HOAc, within the 10 mol%–200 mol% range (entries 9–14), enabled the pinpointing of its optimum quantity (20 mol%) under which condition this transformation was achieved in high yield and 3a was obtained in an 85% yield. When monitoring the reaction at different periods of time, we found that the reaction could reach 85% yield in 30 min (entries 11 and 15–18). The reaction temperature at 100 °C was just optimal as lower temperatures furnished reduced yields of product and higher temperatures did not further improve the yield either (ESI, Table 2†). With a lower catalyst loading, the reaction efficiency deteriorated and gave 3a in an unsatisfactory yield (entries 19 and 20).

Table 1 Optimization of reaction conditions^a

Entry	Additive 1 (mol%)	Additive 2 (mol%)	Time (h)	Yield^b (%)
a Reaction conditions: 1a (47 mg, 0.2 mmol), 2a (53 mg, 0.3 mmol), [Cp*Co(CO)I2] (9.6 mg, 10 mol%), HFIP (2 mL). b Isolated yields. c [Cp*Co(CO)I2] (1 mg, 1 mol%), AgSbF6 (1.4 mg, 2.0 mol%). d [Cp*Co(CO)I2] (4.8 mg, 5.0 mol%), AgSbF6 (6.9 mg, 10 mol%).
1	AgOTf (20)	KOAc (100)	12	44
2	AgOTf (20)	PivOH (100)	12	52
3	AgOTf (20)	HOAc (100)	12	66
4	—	HOAc (100)	12	42
5	AgBF4 (20)	HOAc (100)	12	67
6	AgCO2CF3 (20)	HOAc (100)	12	59
7	AgOTs (20)	HOAc (100)	12	62
8	AgPF6 (20)	HOAc (100)	12	66
9	AgSbF6 (20)	HOAc (100)	12	75
10	AgSbF6 (20)	HOAc (10)	12	81
11	AgSbF6 (20)	HOAc (20)	12	85
12	AgSbF6 (20)	HOAc (50)	12	68
13	AgSbF6 (20)	HOAc (150)	12	70
14	AgSbF6 (20)	HOAc (200)	12	54
15	AgSbF6 (20)	HOAc (20)	0.1	40
16	AgSbF6 (20)	HOAc (20)	0.5	85
17	AgSbF6 (20)	HOAc (20)	1	82
18	AgSbF6 (20)	HOAc (20)	5	83
19^c	AgSbF6 (2)	HOAc (20)	0.5	29
20^d	AgSbF6 (10)	HOAc (20)	0.5	67

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With the optimized conditions in hand, a broad range of acetophenone N-Boc hydrazones 1a–1u were screened to couple with diphenylacetylene 2a, as shown in Scheme 2. First, diverse monosubstituted acetophenone N-Boc hydrazones (1b–1j) which had been prepared beforehand, bearing various electron-rich and electron-deficient groups (F, Cl, Br, I, Me, OMe, CF₃, CO₂Me, and Ph) at the para-positions, all underwent smooth coupling with diphenylacetylene 2a, and the cyclization products (3b–3j) were isolated in yields of 71–89%. Notably, a strong electron-withdrawing group (NO₂) at the para-position of acetophenone N-Boc hydrazone (1k) was tolerable and gave the corresponding isoquinoline product (3k) at a moderate yield (45%). The reaction of meta-substituted acetophenone N-Boc hydrazones 1l and 1m preferentially occurred at the less hindered position to afford the corresponding products 3l (72%) and 3m (69%) in good yields with single and opposite regioisomer selectivity. Also, the substrate 1n bearing a methoxy group at the ortho-position showed weaker reactivity in this reaction to give 3n in an acceptable yield (46%). In addition, benzophenone and 2,3,4-dihydronephthalen N-Boc hydrazone (1o and 1p) were smoothly converted to the corresponding products 3o and 3p in yields of 85% and 86%, respectively. Furthermore, our method is suitable not only for diverse monosubstituted acetophenone N-Boc hydrazones, but also for disubstituted (1q–1t) and even trisubstituted (1u) acetophenone N-Boc hydrazones, and their desired products (3q–3u) can be isolated in good yields and with exclusive regioselectivity.

Scheme 2 Scope of acetophenone N-Boc hydrazones and alkyne substrates. Reaction conditions: 1a–1u (0.2 mmol), 2a–2g (0.3 mmol), [Cp*Co(CO)I₂] (9.6 mg, 10 mol%), AgSbF₆ (13.7 mg, 20 mol%), HOAc (2.4 mg, 20 mol%), HFIP (2 mL). Isolated yields.

Subsequently, we briefly investigated the scope of the alkyne in the coupling with acetophenone N-Boc hydrazone 1a. Symmetrically substituted diarylacetylenes bearing halogen or methyl groups at the para- and meta-positions gave the products 4b–4g in 51%–69% yields (Scheme 2). The use of terminal alkynes, unsymmetrical alkyl/aryl internal alkynes, and dialkyl alkynes gave no corresponding products. And it is surprising to mention that benzaldehyde N-Boc hydrazone 1v with 2a under the same reaction conditions did not afford the expected isoquinoline product 3v (Scheme 3, eqn (1)). Then, we investigated the catalytic efficacy with different N-substitution patterns of acetophenone hydrazone (Scheme 3, eqn (2)). We began our study by using the bulkier N-Ph (1w). However, when we employed a Cp*Co(III)-catalyst with this substrate, no formation of the desired product 3a was observed apart from all the starting materials. But upon switching from the 1w to the N-Ts (1x) and N-Cbz (1y), the desired product 3a could be obtained in poor yields.

Scheme 3 Investigation of the catalytic efficacy with different N-substitution patterns.

Several experiments were briefly performed to understand the reaction mechanism (Scheme 4). To probe the C–H activation process, H/D exchange between acetophenone N-Boc hydrazone 1a and CD₃COOD (100 mol%) was performed (eqn (1)). After stirring for 10 min at 50 °C, 95% of 1a was recovered and only 5% deuterium incorporation was observed, which suggests that under the reaction conditions the C–H bond activation step is irreversible. A small KIE value of 1.2 was obtained (eqn (2)), indicating that C–H activation might not be involved in the rate-determining step. Intermolecular competition between 1c and 1f for the coupling with 2a under the optimized conditions could provide information on the electronic effects of the para-substituent, and ¹H NMR analysis of the mixed product revealed that 3c and 3f were obtained in a 1.2 : 1 ratio (eqn (3)), indicating that the C–H activation probably occurs by a concerted metalation–deprotonation (CMD) mechanism.^15d,19a

Scheme 4 Mechanistic experiments.

On the basis of our preliminary mechanistic experiments and literature precedents,^9–20 the possible reaction pathway for the formation of isoquinolines is depicted in Scheme 5. After formation of the catalytically active cobalt species I, the C–H metalation takes place to form the cobaltacycle II. Then the seven-membered intermediate III can be generated through an alkyne insertion to further undergo an acetic acid-assisted proton migration,²¹ leading to the intermediate IV, followed by intramolecular substitution to form the C–N bond and break the N–N bond with the aid of acid. Finally, the product 3a is formed along with the regeneration of the active catalyst I for a new catalytic cycle.

Scheme 5 Proposed reaction pathway.

In conclusion, we have developed a redox-neutral Cp*Co(III)-catalyzed cyclization of acetophenone N-Boc hydrazones with alkynes for streamlined synthesis of isoquinolines, accomplished via a C–C and C–N bond formation along with N–N bond cleavage. Moreover, this rapid approach can be completed in 30 min with yields up to 85%.

We gratefully acknowledge support from the National Natural Science Foundation of China (21425415, 21274058) and the National Basic Research Program of China (2015CB856303).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6qo00367b

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