Rh(III)-catalyzed atroposelective C–H alkynylation of 1-aryl isoquinolines with hypervalent iodine–alkyne reagents

Abstract

An efficient Rh(III)-catalyzed enantioselective C–H alkynylation of isoquinolines is disclosed. The C–H alkynylation of 1-aryl isoquinolines with hypervalent iodine–alkyne reagents proceeded in DMA at room temperature in the presence of 2.5 mol% chiral SCpRh(III) complex along with 20 mol% AgSbF₆, providing axially chiral alkynylated 1-aryl isoquinolines in excellent yields (up to 93%) and enantioselectivity (up to 95% ee). The diverse transformations of the product further enhance the potential utility of this reaction.

---

Hypervalent iodine reagents (HIRs) have been established as versatile and useful reagents for synthetic organic transformations due to their exceptional reactivity.¹ Among them, ethynylbenziodoxolone (EBX) reagent is one of the most widely used hypervalent iodine reagents for the direct alkynylation of heteroatom or carbon nucleophiles.² In particular, great achievements have been made in transition-metal-catalyzed C–H alkynylation reactions by taking advantage of EBX reagents as the coupling partners (Scheme 1a).³ In 2009, pioneering works on gold or palladium-catalyzed C–H alkynylation of electron-rich aromatic substrates including indoles, pyrroles and anilines with hypervalent alkynyl iodine reagents were developed by Waser and co-workers.^3d Later on, Loh and coworkers reported an elegant example of rhodium-catalyzed electronically reversed Sonogashira coupling of electron-poor arenes, affording the alkynyl benzamide products in up to 99% yield.^3e Shortly afterwards, Li and coworkers developed efficient Rh(III)- and Ir(III)-catalyzed ortho C–H alkynylation reactions of diversified arenes using hypervalent iodine–alkyne reagents.^3j Both electron-poor and electron-rich arenes bearing different directing groups are viable substrates in this transformation. Although much progress has been accomplished, it remains challenging to develop Rh(III)-catalyzed enantioselective C–H alkynylation by employing EBX reagents.

Scheme 1 Transition-metal-catalyzed C–H alkynylation reactions with EBX reagents.

The synthesis of axially chiral biaryls has been extensively investigated since they broadly exist in natural products, pharmaceuticals, biologically active molecules, chiral ligands, and organocatalysts.⁴ Among these methods, the atroposelective C–H functionalization of achiral biaryls represents one of the most efficient and straightforward approaches to access axially chiral biaryls.⁵ In this regard, the synthesis of axially chiral alkyne-functionalized biaryls has been widely explored via transition-metal-catalyzed atroposelective C–H alkynylation.⁶ In 2018, Shi and coworkers demonstrated a highly practical and efficient strategy for the construction of a broad range of enantiomerically enriched axially chiral biaryls in excellent yields (up to 99%) and enantioselectivity (up to >99% ee) through Pd-catalyzed atroposelective C–H alkynylation.⁷ Later on, they found that the atropisomers containing one or even two five-membered rings connected through C–C or C–N bonds were compatible with the same strategy.⁸ While these elegant achievements exhibited the feasibility of catalytic asymmetric synthesis of alkynyl-containing atropisomers, the application of EBX reagents in transition-metal-catalyzed atroposelective C–H alkynylation remains undeveloped. With our continuous interest in Rh-catalyzed asymmetric C–H functionalization and synthesis of biaryl atropisomers,⁹ we envisioned that Rh-enabled enantioselective C–H alkynylation of 1-aryl isoquinoline with EBX might efficiently furnish enantio-enriched alkynyl biaryls. Herein, we report the highly atroposelective synthesis of 1-aryl isoquinolines via CpRh-catalyzed C–H alkynylation reaction. This strategy provides efficient access to a wide range of axially chiral alkynylated isoquinolines.

We commenced our studies with the reaction of 1-(naphthalen-1-yl)benzo[h]isoquinoline 1a with 1-[(triisopropylsilyl)ethynyl]-1,2-benziodoxol-3(1H)-one (TIPS-EBX) 2a at 80 °C in the presence of 5 mol% of (S)-Rh1,^9d 20 mol% of AgSbF₆, and 2 equivalents of Cu(OAc)₂ in ^tAmylOH. Gratifyingly, the desired axially chiral alkynylated isoquinoline 3aa was obtained in 97% yield and 59% ee (Table 1, entry 1). 3aa was proved to be conformationally stable, and no erosion of its ee value was observed after heating at 170 °C for 10 h. Encouraged by these preliminary results, various chiral CpRh catalysts were screened, and (S)-Rh1 was confirmed to be the optimal one (entries 2–3, for complete catalyst screening, see Table S1, ESI†). The solvent effect revealed that DMA was the optimal choice, giving rise to 3aa in 86% yield and 72% ee (see Table S2 for details, ESI†). The utilization of other silver salts including AgNTf₂, AgOTf and AgPF₆etc. has no obvious influence on the enantioselectivity (see Table S3 for details, ESI†). In addition, other reaction parameters such as copper salts, concentration, and additives were investigated, and the results in terms of yield and enantioselectivity were not further improved (see Tables S4–S6 for details, ESI†). Notably, when the reaction was performed at room temperature, the enantioselectivity was increased to 78% ee. Further lowering the reaction temperature to 0 °C resulted in a dramatically decreased yield (51%, 88% ee) (see Table S7 for details, ESI†). Subsequently, the TIPS-protected alkynylation reagents 2b–2d were screened (entries 5–7, see Table S8 for other alkynylation reagents, ESI†). The use of EBX reagent 2c¹⁰ bearing gem-ditrifluoromethyl groups gave the best results in terms of yield and enantioselectivity (entry 6, 88% yield, 84% ee). It is noteworthy that TIPS-protected alkynyl bromide (2d) was also compatible in this reaction with slightly decreased yield and enantioselectivity (entry 7, 63% yield, 80% ee). The ee value of 3aa could be further improved when this C–H alkynylation reaction with 2c was carried out in the absence of Cu(OAc)₂. (Entry 8, 82% yield, 87% ee. See Table S10 for details, ESI†) Prolonging the reaction time to 48 h gave the optimal reaction conditions, affording 3aa in 88% yield and 87% ee (entry 9). It is noteworthy that this reaction could be accomplished under an air atmosphere, leading to the alkynylated product in 52% yield and 90% ee (entry 10). Overall, the optimal reaction conditions were identified as the following: 1a (1 equiv.), 2c (2 equiv.), (S)-Rh1 (2.5 mol%), AgSbF₆ (20 mol%) under argon in DMA at room temperature for 48 h.

Table 1 Optimization of the reaction conditions^a

Entry	[Rh]	2	Solvent	T (°C)	t (h)	Yield^b (%)	ee^c (%)
a Reaction conditions: 1a (0.05 mmol), 2 (0.1 mmol), [Rh] (5 mol%), AgSbF6 (20 mol%), Cu(OAc)2 (0.1 mmol) in solvent (0.25 mL). b Isolated yield. c Determined by HPLC analysis with a chiral stationary phase. d No Cu(OAc)2. e Under air.
1	(S)-Rh1	2a	^tAmylOH	80	12	97	59
2	(S)-Rh2	2a	^tAmylOH	80	12	91	33
3	(S)-Rh3	2a	^tAmylOH	80	12	40	−13
4	(S)-Rh1	2a	DMA	80	12	86	72
5	(S)-Rh1	2b	DMA	80	24	30	12
6	(S)-Rh1	2c	DMA	rt	24	88	84
7	(S)-Rh1	2d	DMA	rt	24	63	80
8^d	(S)-Rh1	2c	DMA	rt	24	82	87
9^d	(S)-Rh1	2c	DMA	rt	48	88	87
10^d^e	(S)-Rh1	2c	DMA	rt	48	52	90

---

With the optimal reaction conditions in hand, the atroposelective C–H alkynylation of substituted 1-aryl isoquinolines 1 with 2c was first investigated (Scheme 2). The isoquinolines bearing either a 4-methyl or 4-methoxy group on the naphthalene ring gave the desired products 3ba–3ca in 79% yield and good enantioselective control (82–94% ee). The substrates bearing F, Cl, Br and a phenyl group on the 4-position of the naphthalene ring were also well compatible, affording 3da–3ga with good yields and moderate to excellent enantioselectivity (80–85% yields, 43–90% ee). It is noteworthy that the polycyclic naphthalene substrates were also tolerated, furnishing products in good to excellent yields and moderate to excellent enantioselectivity (3ha–3ja, 84–91% yields, 61–90% ee). The benzoisoquinoline substrates containing heteroaromatic rings were compatible with this reaction, giving 3ka in 86% yield with 90% ee and 3la in 93% yield with 79% ee, respectively. Employing the π-extended benzoisoquinoline 1m as a substrate led to the alkynylated atropisomer 3ma in 81% yield with 65% ee. In addition, the isoquinoline substrate 1n furnished 3na with poor enantioselectivity, likely due to the less steric effect (3n, 85% yield, 34% ee). Notably, a gram-scale reaction of 1a with 2c was conducted under the standard conditions, providing 3aa in 90% yield (1.31 g) with 76% ee.

Scheme 2 Rh-catalyzed C–H alkynylation reactions with EBX reagents. ^aReaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), (S)-Rh1 (2.5 mol%), and AgSbF₆ (20 mol%) in DMA (1 mL). ^bIsolated yield. ^cThe ee values were determined by HPLC analysis on a chiral stationary phase. ^dReaction conditions: 1 (3 mmol), 2 (6 mmol), (S)-Rh1 (2.5 mol%), and AgSbF₆ (20 mol%) in DMA (15 mL).

Next, the benzoisoquinolines bearing ortho-substituted phenyl groups were explored (Scheme 2). When substrates bearing 2-methyl or 2-ethyl groups on the benzene ring were applied in this reaction, 3oa–3qa were obtained smoothly with moderate to excellent enantioselectivity (85–89% yields, 79–89% ee). The ortho-methoxy-substituted substrates 1r–1s gave the desired products 3ra–3sa in 63–92% yields and 61–71% ee. Interestingly, the ortho NO₂-substituted substrate gave the best ee value, and this is probably due to the nitro group being coordinated with rhodium (3ta, 80% yield, 95% ee). It should be noted that the ortho Cl-substituted substrate was also compatible with this reaction (3ua, 90% yield, 78% ee). In addition, the protecting group TIPS of 2c replaced by TBS (t-butyldimethylsilyl) resulted in a dramatically decreased yield (3ae, 24% yield, 76% ee).

To demonstrate the potential utility of 3aa, the synthetic applications of the alkynylation product were investigated. By treatment of 3aa with TBAF in THF at room temperature, the TIPS group could be readily removed to afford the terminal alkyne 4 in 97% yield with 87% ee (Scheme 3a). Then, 4 was utilized as a key intermediate for the synthesis of various axially chiral 1-aryl isoquinolines. The Sonogashira coupling reaction of 4 was carried out to afford the phenylacetylene substituted product 5 in 96% yield. The absolute configuration of 5 was assigned as R_a according to the reported literature (Scheme 3b).⁹ⁱ The configurations of other products were assigned by analogy. Highly selective semi-hydrogenation of alkyne was achieved in 74% yield (Scheme 3c).¹¹ Moreover, the Cu(I)-catalyzed click reaction of 4 with benzyl azide was performed under mild conditions to give triazole product 7 in 86% yield and 86% ee (Scheme 3d).¹² Finally, the N-oxidation reaction of 4 treated with m-CPBA furnished N-oxide 8 in 93% yield without loss of enantioselectivity (Scheme 3e).

Scheme 3 Representative derivatizations.

To shed light on the mechanism of this C–H alkynylation reaction, H/D exchange of 1a was performed in the presence of D₂O under standard conditions. No deuterium incorporation indicated that the C–H cleavage is irreversible (Scheme 4a). The kinetic isotope effect was then measured from the alkynylation reaction of 1a-D₁ and 1a, and a large KIE value of 4.05 suggests that the C–H bond activation might be involved in the turnover-limiting step (Scheme 4b).¹³

Scheme 4 Mechanistic studies.

Based on the above mechanistic studies and previous report,¹⁴ a plausible mechanism for atroposelective C–H alkynylation is proposed (Fig. S3, ESI†). Following path a, the chiral CpRh complex firstly undergoes oxidative addition with 2c to form the CpRh(V) complex I. Subsequently, the cyclometalation of 1a with the active CpRh(V) complex I affords an intermediate III, along with the generation of alcohol 9. Finally, the alkanylated product 3aa is released after the reductive elimination of rhodacycle III and regenerates the Rh(III) catalyst. Another pathway involving the C–H activation of 1-aryl benzoisoquinoline first, followed by oxidative addition with 2c cannot be completely excluded at present.

In summary, we have developed highly atroposelective synthesis of alkynylated 1-aryl isoquinolines based on Rh(III)-catalyzed C–H alkynylation of 1-aryl isoquinolines with hypervalent iodine–alkyne reagents. A broad scope of substrates has been defined, and the C–H Sonogashira coupling reaction proceeded in excellent yields and enantioselectivity under mild reaction conditions. It is noteworthy that diverse transformations were realized for the synthesis of structurally diverse 1-aryl isoquinolines with potential applications. Further development of transition-metal-catalyzed enantioselective C–H functionalization reactions for the construction of axially chiral biaryls is underway in our laboratory.

This work is supported by the National Key R&D Program of China (2021YFA1500100) and the National Natural Science Foundation of China (21821002, 92256302, 22071260). S.-L. Y. acknowledges the support from the New Cornerstone Science Foundation.

Conflicts of interest

The authors declare no competing financial interest.

Notes and references

1. For reviews on hypervalent iodine reagents, see: (a) V. V. Zhdankin and P. J. Stang, Chem. Rev., 2002, 102, 2523–2584; (b) V. V. Zhdankin and P. J. Stang, Chem. Rev., 2008, 108, 5299–5358; (c) J. Charpentier, N. Fruh and A. Togni, Chem. Rev., 2015, 115, 650–682; (d) A. Yoshimura and V. V. Zhdankin, Chem. Rev., 2016, 116, 3328–3435; (e) D. P. Hari, P. Caramenti and J. Waser, Acc. Chem. Res., 2018, 51, 3212–3225; (f) A. Parra, Chem. Rev., 2019, 119, 12033–12088; (g) X. Zhang, K. Zhao and Z. Gu, Acc. Chem. Res., 2022, 55, 1620–1633; (h) X. Peng, A. Rahim, W. Peng, F. Jiang, Z. Gu and S. Wen, Chem. Rev., 2023, 123, 1364–1416.
2. For reviews on ethynylbenziodoxolone (EBX) reagents, see: (a) S. Banerjee, V. W. Bhoyare and N. T. Patil, Chem. Commun., 2020, 56, 2677–2690; (b) E. Le Du, T. Duhail, M. D. Wodrich, R. Scopelliti, F. Fadaei-Tirani, E. Anselmi, E. Magnier and J. Waser, Chem. – Eur. J., 2021, 27, 10979–10986; (c) I. A. Mironova, D. M. Noskov, A. Yoshimura, M. S. Yusubov and V. V. Zhdankin, Molecules, 2023, 28, 2136; (d) E. Le Du and J. Waser, Chem. Commun., 2023, 59, 1589–1604 . For selected examples on ethynylbenziodoxolone (EBX) reagents, see: ; (e) J. P. Brand, C. Chevalley, R. Scopelliti and J. Waser, Chem. – Eur. J., 2012, 18, 5655–5666; (f) C. C. Chen and J. Waser, Chem. Commun., 2014, 50, 12923–12926; (g) F. Le Vaillant, T. Courant and J. Waser, Angew. Chem., Int. Ed., 2015, 54, 11200–11204; (h) D. P. Hari and J. Waser, J. Am. Chem. Soc., 2016, 138, 2190–2193; (i) S. Banerjee and N. T. Patil, Chem. Commun., 2017, 53, 7937–7940; (j) D. P. Hari and J. Waser, J. Am. Chem. Soc., 2017, 139, 8420–8423; (k) E. Voutyritsa, M. Garreau, M. G. Kokotou, I. Triandafillidi, J. Waser and C. G. Kokotos, Chem. – Eur. J., 2020, 26, 14453–14460.
3. For reviews on transition-metal-catalyzed C-H alkynylation reactions by employing EBX reagents, see: (a) X. Li, W. Ouyang, J. Nie, S. Ji, Q. Chen and Y. Huo, ChemCatChem, 2020, 12, 2358–2384; (b) A. Suseelan Sarala, S. Bhowmick, R. L. de Carvalho, S. A. Al-Thabaiti, M. Mokhtar, E. N. da Silva Junior and D. Maiti, Adv. Synth. Catal., 2021, 363, 4994–5027; (c) D. Chandra, A. K. Dhiman, D. Parmar and U. Sharma, Cat. Rev.-Sci. Eng., 2022, 64, 716–788 . For selected examples on transition-metal-catalyzed C–H alkynylation reactions by employing EBX reagents, see: ; (d) J. P. Brand, J. Charpentier and J. Waser, Angew. Chem., Int. Ed., 2009, 48, 9346–9349; (e) C. Feng and T.-P. Loh, Angew. Chem., Int. Ed., 2014, 53, 2722–2726; (f) K. D. Collins, F. Lied and F. Glorius, Chem. Commun., 2014, 50, 4459–4461; (g) C. Feng, D. Feng and T.-P. Loh, Chem. Commun., 2014, 50, 9865–9868; (h) J. Jeong, P. Patel, H. Hwang and S. Chang, Org. Lett., 2014, 16, 4598–4601; (i) C. Feng, D. Feng, Y. Luo and T.-P. Loh, Org. Lett., 2014, 16, 5956–5959; (j) F. Xie, Z. Qi, S. Yu and X. Li, J. Am. Chem. Soc., 2014, 136, 4780–4787; (k) H. Wang, F. Xie, Z. S. Qi and X. W. Li, Org. Lett., 2015, 17, 920–923; (l) P. Finkbeiner, U. Kloeckner and B. J. Nachtsheim, Angew. Chem., Int. Ed., 2015, 54, 4949–4952; (m) Y. Li and J. Waser, Angew. Chem., Int. Ed., 2015, 54, 5438–5442; (n) A. C. Shaikh, D. R. Shinde and N. T. Patil, Org. Lett., 2016, 18, 1056–1059; (o) G. N. Hermann, M. T. Unruh, S.-H. Jung, M. Krings and C. Bolm, Angew. Chem., Int. Ed., 2018, 57, 10723–10727; (p) J. Zhang, M. Wang, H. Wang, H. Xu, J. Chen, Z. Guo, B. Ma, S.-R. Ban and H.-X. Dai, Chem. Commun., 2021, 57, 8656–8659.
4. For reviews, see: (a) W. Tang and X. Zhang, Chem. Rev., 2003, 103, 3029–3070; (b) J. Chang, J. Reiner and J. Xie, Chem. Rev., 2005, 105, 4581–4609; (c) M. C. Kozlowski, B. J. Morgan and E. C. Linton, Chem. Soc. Rev., 2009, 38, 3193–3207; (d) G. Bringmann, T. Gulder, T. A. M. Gulder and M. Breuning, Chem. Rev., 2011, 111, 563–639; (e) L. Pu, Acc. Chem. Res., 2012, 45, 150–163; (f) M. P. Carroll and P. J. Guiry, Chem. Soc. Rev., 2014, 43, 819–833; (g) E. Kumarasamy, R. Raghunathan, M. P. Sibi and J. Sivaguru, Chem. Rev., 2015, 115, 11239–11300.
5. For reviews on the synthesis of axially chiral biaryls by asymmetric C–H functionalizations, see: (a) J. Wencel-Delord, A. Panossian, F. R. Leroux and F. Colobert, Chem. Soc. Rev., 2015, 44, 3418–3430; (b) G. Liao, T. Zhou, Q. J. Yao and B.-F. Shi, Chem. Commun., 2019, 55, 8514–8523; (c) Q. Wang, Q. Gu and S.-L. You, Acta Chim. Sin., 2019, 77, 690–704.
6. For reviews, see: (a) S. Toyota, Chem. Rev., 2010, 110, 5398–5424; (b) Z.-F. Zhou, M. Menna, Y. S. Cai and Y. W. Guo, Chem. Rev., 2015, 115, 1543–1596 . For selected examples, see: ; (c) C. J. Smedley, G. Li, A. S. Barrow, T. L. Gialelis, M.-C. Giel, A. Ottonello, Y. Cheng, S. Kitamura, D. W. Wolan, K. B. Sharpless and J. E. Moses, Angew. Chem., Int. Ed., 2020, 59, 12460–12469; (d) B. Song, R. Zhang, R. Hu, X. Chen, D. Liu, J. Guo, X. Xu, A. Qin and B. Z. Tang, Adv. Sci., 2020, 7, 2000465; (e) A. S.-Y. Law, L. C.-C. Lee, K. K.-W. Lo and V. W.-W. Yam, J. Am. Chem. Soc., 2021, 143, 5396–5405.
7. G. Liao, Q.-J. Yao, Z.-Z. Zhang, Y.-J. Wu, D.-Y. Huang and B.-F. Shi, Angew. Chem., Int. Ed., 2018, 57, 3661–3665.
8. S. Zhang, Q.-J. Yao, G. Liao, X. Li, H. Li, H.-M. Chen, X. Hong and B.-F. Shi, ACS Catal., 2019, 9, 1956–1961.
9. For reviews, see: (a) C.-X. Liu, W.-W. Zhang, S.-Y. Yin, Q. Gu and S.-L. You, J. Am. Chem. Soc., 2021, 143, 14025–14040; (b) C.-X. Liu, S.-Y. Yin, F. Zhao, H. Yang, Z. Feng, Q. Gu and S.-L. You, Chem. Rev., 2023, 123, 10079–10134; (c) Y.-M. He, Y.-Z. Cheng, Y. Duan, Y.-D. Zhang, Q.-H. Fan, S.-L. You, S. Luo, S.-F. Zhu, X.-F. Fu and Q.-L. Zhou, CCS Chem., 2023, 5, 2685–2716 . For selected examples, see: ; (d) J. Zheng, W.-J. Cui, C. Zheng and S.-L. You, J. Am. Chem. Soc., 2016, 138, 5242–5245; (e) Q. Wang, Z.-J. Cai, C.-X. Liu, Q. Gu and S.-L. You, J. Am. Chem. Soc., 2019, 141, 9504–9510; (f) Q. Wang, W.-W. Zhang, H. Song, J. Wang, C. Zheng, Q. Gu and S.-L. You, J. Am. Chem. Soc., 2020, 142, 15678–15685; (g) W.-W. Zhang, C.-X. Liu, P. Yang, S.-Z. Zhang, Q. Gu and S.-L. You, Org. Lett., 2022, 24, 564–569; (h) W.-W. Zhang, Q. Wang, S.-Z. Zhang, C. Zheng and S.-L. You, Angew. Chem., Int. Ed., 2023, 62, e202214460; (i) D.-S. Zheng, W.-W. Zhang, Q. Gu and S.-L. You, ACS Catal., 2023, 13, 5127–5134; (j) D.-S. Zheng, J. Zheng, Q. Wang, Q. Gu and S.-L. You, Chin. J. Chem., 2023, 41, 2684–2690; (k) D.-S. Zheng, P.-P. Xie, F. Zhao, C. Zheng, Q. Gu and S.-L. You, ACS Catal., 2024, 14, 6009–6015.
10. V. V. Zhdankin, C. J. Kuehl, A. P. Krasutsky, J. T. Bolz and A. J. Simonsen, J. Org. Chem., 1996, 61, 6547–6551.
11. (a) A. M. Whittaker and G. Lalic, Org. Lett., 2013, 15, 1112–1115; (b) K. Semba, T. Fujihara, T. Xu, J. Terao and Y. Tsuji, Adv. Synth. Catal., 2012, 354, 1542–1550.
12. V. Hornillos, A. Ros, P. Ramírez-López, J. Iglesias-Sigüenza, R. Fernández and J. M. Lassaletta, Chem. Commun., 2016, 52, 14121–14124.
13. E. M. Simmons and J. F. Hartwig, Angew. Chem., Int. Ed., 2012, 51, 3066–3072.
14. (a) S. Liu, X. Qi, L.-B. Qu, R. Bai and Y. Lan, Catal. Sci. Technol., 2018, 8, 1645–1651; (b) S. Vasquez-Cespedes, X. Wang and F. Glorius, ACS Catal., 2018, 8, 242–257.

---

Footnote

† Electronic supplementary information (ESI) available: Experimental procedures and characterization data of all compounds. See DOI: https://doi.org/10.1039/d4cc01785d

---