Enantioselective Synthesis of Axially Chiral 1-Arylisoquinolines by Iridium(I)-Catalyzed Hydroarylation of Alkynes

Abstract

Ir(I)-catalyzed atroposelective hydroarylation of alkynes with 1-arylisoquinolines through C–H functionalization was realized. In the presence of 5 mol% of [Ir(cod)Cl]₂ and 10 mol% of QUINOX-P, a wide range of axially chiral alkenylated biaryls were obtained in up to 98% yield and 97% ee. Notably, only one equivalent of the alkyne was required to guarantee a high efficiency of this C–H functionalization process. This reaction exhibits excellent functional-group tolerance under mild conditions.

Key words

alkynes - isoquinolines - axial chirality - C–H functionalization - iridium catalysis - asymmetric synthesis

Transition-metal-catalyzed enantioselective C–H functionalization represents one of the most valuable and straightforward routes to optically active molecules by direct transformations of C–H compounds.[1] In this regard, significant advances have been made over the past decade in the enantioselective construction of axially chiral compounds through C–H functionalization.[2] [3] Of particular note, axially chiral pyridine and isoquinoline derivatives have received considerable attention due to their wide range of applications in chiral ligands and catalysts (Figure [1]).[4]

In 2000, Murai and co-workers developed the first example of a rhodium(I)-catalyzed atroposelective C–H alkylation of arylpyridines with ethylene, albeit with moderate enantioselectivity.[5] In 2014, our group reported an enantioselective oxidative Heck reaction of 1-arylisoquinolines with olefins by using a chiral cyclopentadienyl rhodium(III) catalyst, resulting in axially chiral alkenylated biaryls in up to 99% yield and 86% ee.[6] Soon after, related atroposelective C–H arylation reactions with either aryl halides or electron-rich heteroarenes were realized to provide axially chiral arylated biaryls with high enantioselectivity (Scheme [1a]).[7] Nevertheless, the development of novel atroposelective C–H functionalization reactions to afford structurally diverse axially chiral isoquinolines remains highly desirable.

Figure 1 Axially chiral pyridine- and isoquinoline-containing ligands

Scheme 1 Synthesis of axially chiral 1-arylisoquinolines by atroposelective C–H functionalization

Scheme 2 Scope of the Ir(I)-catalyzed C–H hydroarylation of alkynes

Hydroarylation of alkyne featuring a 100% atom economy has received much attention, as it provides facile and direct access to functionalized alkenes from simple arenes and alkynes. Significant advances have been made by employing various transition-metal catalysts.[8] Furthermore, Lewis acid-catalyzed enantioselective alkyne hydroarylation reactions have also been developed in recent years, most of which proceed through intramolecular Friedel–Crafts-type reactions.[9] Recently, significant progress has been made on the enantioselective hydroarylation of alkynes by directing-group-assisted arene C–H functionalization. In 2021, Hou and co-workers reported an enantioselective hydroarylation of quinoline- and pyridine-substituted ferrocenes with alkynes in the presence of a half-sandwich scandium catalyst, providing an array of planar-chiral ferrocenes.[10] Later, an Ir-catalyzed enantioselective B–H alkenylation for the synthesis of chiral-at-cage o-carboranes was realized by Xie, Qiu, and co-workers, which further enriched the construction of novel chiral elements.[11] However, the related C–H functionalization by alkynes toward axially chiral molecules has been less-well investigated.[12] Considering the importance of axially chiral 1-arylisoquinolines and our continuing interest in the synthesis of biaryl atropisomers,[6] [7] [13] we envisioned that isoquinoline-directed hydroarylation of alkynes by C–H functionalization might be feasible as a means of providing axially chiral alkenylated 1-arylisoquinolines with high atom economy (Scheme [1b]). Here, we report the details of this study.

Initially, the hydroarylation of diarylalkyne 2a with 1-(1-naphthyl)benzo[h]isoquinoline (1a) was carried out at 80 °C in the presence of 5 mol% [Ir(cod)Cl]₂, 10 mol% of (R)-BINAP, and 20 mol% of sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (NaBAr^F) in toluene (0.1 N). To our delight, the alkenylated product 3aa [14] was obtained in 75% NMR yield and 63% ee (Table [1], entry 1). Encouraged by these preliminary results, we tested several other phosphine ligands (L2–6) (entries 2-6). SEGPHOS (L2) gave a comparable yield and enantioselectivity (entry 2; 78% NMR yield, 61% ee), whereas SDP (L3)[15] gave only a 5% NMR yield (entry 3). Pleasingly, the P-chiral ligand QUINOX-P (L4)[16] exhibited excellent enantioselective induction, giving 3aa in 66% NMR yield and 94% ee (entry 4). However, the other P-chiral ligands L5 and L6 were found to be inactive for this reaction (entries 5 and 6). Therefore, QUINOX-P was used for further optimizations (see the Supporting Information for complete ligand screening). Investigation of the solvent effect (entries 7–12) revealed that THF gave the best results in terms of yield and enantioselectivity (entry 7; 70% NMR yield, 95% ee). Notably, by lowering the amount of alkyne to one equivalent, the yield of 3aa improved to 93% (entry 14; 93% NMR yield, 96% ee), whereas five equivalents of alkyne were used in a recent related work.[12] In addition, a 97% isolated yield and 96% ee were obtained when the reaction was performed in 0.2 mmol scale at a higher concentration (0.2 N; 1 mL THF) (entry 15). Overall, the optimized reaction conditions were identified as the following: 1a (1.0 equiv), 2a (1.0 equiv), [Ir(cod)Cl]₂ (5 mol%), L4 (10 mol%), and NaBAr^F (20 mol%) in THF (0.2 N) at 80 °C under Ar.

Table 1 Optimization of the Reaction Conditions^a

Entry	Ligand	Solvent	Yieldb (%)	eec (%)
1	L1	toluene	75	63
2	L2	toluene	78	61
3	L3	toluene	5	81
4	L4	toluene	66	94
5	L5	toluene	8	92
6	L6	toluene	trace	–
7	L4	THF	70	95
8	L4	2-methyltetrahydrofuran	49	93
9	L4	1,4-dioxane	77	94
10	L4	DME	trace	–
11	L4	DCE	35	95
12	L4	PhCl	27	94
13d	L4	THF	92	96
14e	L4	THF	93	96
15f	L4	THF	97g	96

^a Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), [Ir(cod)Cl]₂ (5 mol%), ligand (10 mol%), NaBAr^F (20 mol%), solvent (1.0 mL), 80 °C, under Ar, 10 h.

^b Determined by ¹H NMR analysis of the crude reaction mixture with CH₂Br₂ as an internal standard.

^c Determined by HPLC analysis on a chiral stationary phase.

^d 2a (1.5 equiv, 0.15 mmol) were used.

^e 2a (1.0 equiv, 0.10 mmol) were used.

^f 1a (0.2 mmol), 2a (0.2 mmol), [Ir(cod)Cl]₂ (5 mol%), L4 (10 mol%), NaBAr^F (20 mol%), THF (1.0 mL), 80 °C, under Ar, 10 h.

^g Isolated yield.

With the optimized conditions in hand, we examined the Ir(I)-catalyzed atroposelective hydroarylation with various 1-arylbenzoisoquinoline derivatives 1 (Scheme [2]).[17] A variety of 1-arylisoquinolines worked well with bis(4-methoxyphenyl)acetylene (2a), generating the desired alkenylated products in moderate to excellent yields and enantioselectivities. 1-Naphthylbenzoisoquinolines bearing a 4-methyl, 4-methoxy, or 4-chloro group on the naphthalene ring were compatible in this reaction, and gave the corresponding products 3ba–da in yields of 67–96% with 94–97% ee. The reactions of acenaphthyl and pyrenyl derivatives 1e and 1f gave the axially chiral alkenylated products 3ea and 3fa, respectively, in yields of 92 and 89% with 96 and 95% ee. In addition, dibenzofuryl or ortho-methylphenyl (benzo)isoquinolines were also suitable substrates, giving 3ga–ia in yields of 61–81% and 89–96% ee. To our delight, 1-naphthyl isoquinolines with various substituents on the naphthalene ring gave products 3ja–ma in yields of 68–98% and 85–89% ee. Notably, the reaction proceeded well with a challenging 2-naphthylpyridine substrate, providing 3na in 81% yield with 83% ee. With 1-(1-naphthyl)benzo[h]isoquinoline (1a) as the coupling partner, an array of alkynes were well tolerated, and the desired alkenylated products 3ab–ae were obtained in yields of 74–90% with 95–97% ee. The absolute configurations of products 3ja and 3na were assigned as S _a by comparing the signs of their optical rotations with those of the known compounds.[12] The absolute configurations of other products were assigned by analogy.

In summary, we have developed an Ir(I)-catalyzed atroposelective hydroarylation of alkynes with 1-arylisoquinoline derivatives. This reaction proceeded smoothly in the presence of 5 mol% of [Ir(cod)Cl]₂ and 10 mol% of QUINOX-P. The axial chiral alkenylated products were obtained in excellent yields (≤98%) and high enantioselectivities (≤97% ee). The reaction conditions feature only one equivalent of alkyne, and can accommodate a wide range of 1-arylisoquinolines and alkynes. Further studies on atroposelective C–H functionalization reactions are ongoing in our laboratory.

Conflict of Interest

The authors declare no conflict of interest.

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• 14 (S _a,E)-1-[2-(1,2-Bis(4-methoxyphenyl)vinyl]-1-naphthyl)benzo[h]isoquinoline (3aa) Yellow foam; yield: 105.7 mg (97%, 96% ee); [α]_D ²⁴ –394.9 (c = 0.2, CHCl₃). HPLC [Chiralpak AD-H column (4.6 × 250 mm), hexane/i-PrOH (90:10); flow rate: 1.0 mL/min, λ = 254 nm, 25 ℃]. t _R (minor) = 8.23 min; t _R (major) = 23.86 min. IR (ATR): = 2925, 2854, 1605, 1509, 1462, 1291, 1247, 1176, 1033, 853, 826, 752, 669 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.57 (d, J = 5.2 Hz, 1 H), 8.01 (d, J = 8.4 Hz, 1 H), 7.95 (d, J = 8.0 Hz, 1 H), 7.83–7.75 (m, 2 H), 7.62 (d, J = 8.4 Hz, 1 H), 7.57 (d, J = 8.8 Hz, 1 H), 7.52–7.46 (m, 2 H), 7.46–7.41 (m, 2 H), 7.38 (d, J = 8.4 Hz, 1 H), 7.28–7.19 (m, 1 H), 7.08–7.00 (m, 1 H), 6.48–6.48 (m, 4 H), 6.27 (d, J = 8.4 Hz, 2 H), 6.16 (s, 1 H), 6.09 (d, J = 8.4 Hz, 2 H), 3.62 (s, 3 H), 3.52 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 158.0, 157.7, 157.1, 143.6, 140.7, 140.2, 139.1, 137.8, 133.5, 133.1, 132.2, 132.1, 131.9, 130.9, 130.6, 130.22, 130.17, 129.6, 129.3, 128.7, 128.4, 128.1, 126.92, 126.90, 126.86, 126.6, 126.4, 126.3, 126.0, 125.5, 120.9, 113.1, 112.8, 55.1, 55.0. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₃₉H₃₀NO₂: 544.2271; found: 544.2265.
• 15 Xie J.-H, Wang L.-X, Fu Y, Zhu S.-F, Fan B.-M, Duan H.-F, Zhou Q.-L. J. Am. Chem. Soc. 2003; 125: 4404
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• 17 1-(2-[1,2-Diarylvinyl]-1-naphthyl)benzo[h]isoquinolines 3: General Procedure Under an argon atmosphere, a flame-dried 10 mL Schlenk tube was charged with [Ir(cod)Cl]₂ (6.7 mg, 0.01 mmol, 5 mol%), (S,S)-QUINOX-P (6.6 mg, 0.02 mmol, 10 mol%) and anhyd THF (1.0 mL), and the resulting solution was stirred for 10 min at rt. Then, isoquinoline 1 (0.2 mmol), alkyne 2 (0.2 mmol), and NaBAr^F (35.4 mg, 0.04 mmol, 20 mol%) were added under argon and the tube was heated at 80 °C for 10–24 h. The mixture was then cooled to rt and the crude product was purified by preparative TLC (PE–EtOAc, 5:1).

Publication History

Received: 10 January 2023

Accepted after revision: 29 January 2023

Accepted Manuscript online:
29 January 2023

Article published online:
22 February 2023