Late-Stage C–H Arylation of Azepinoindole via Pd/Cu Catalysis: A Step Efficient and Convergent Synthesis of Rucaparib

Abstract

The C–H arylation of indoles holds the promise to shorten synthetic routes in the production of pharmaceuticals. However, late-stage C–H activation reactions often rely on the presence of protecting groups or stoichiometric metal additives. The regiospecific C–H arylation of a highly functionalized azepino[5,3,4-cd]indole scaffold lacking directing groups via Pd(II) and Cu(II) co-catalysis is reported. The direct C–H coupling was demonstrated in the convergent synthesis of rucaparib, an FDA approved anticancer drug.

Biographical Sketches

Igor Beckers, born in Leuven (Belgium) in 1996, is currently a Ph.D. researcher at the Department of Molecular and Microbial systems of KU Leuven. He obtained a bachelor’s degree in Bioscience Engineering (Cell and Gene technology) at KU Leuven, which included a six-month stay at the Norwegian University for Science and Technology (NTNU) in Trondheim (Norway). He then received his master’s degree in Catalytic Technology and conducted his thesis research on aerobic C–C coupling via metal-catalyzed ­C–H­ activation under the guidance of Prof. Dirk De Vos. His current research focuses on the rational design of innovative ­C–H­ activation catalysts for the efficient synthesis of pharmaceuticals.

Galahad O’Rourke is a student at the center for Membrane Separations, Adsorption, Catalysis and Spectroscopy for Sustainable Solutions (cMACS). He holds master’s degrees in chemistry and medical physics. His initial research experience was at the University College Dublin and KU Leuven, in the asymmetric synthesis of tertiary alcohols and investigating magnetically recoverable palladium catalysts for cross-coupling reactions, respectively. Thereafter, Galahad started working on the chemical recycling of plastic waste in his Ph.D. research under the guidance of Prof. Dirk De Vos.

Dirk De Vos (°1967) is a Full Professor at KU Leuven since 2006. After a Ph.D. with Pierre Jacobs on inclusion complexes in zeolites and a post-doc at Purdue University with Thomas Bein, he started his career at KU Leuven. His main interests are organic catalytic reactions, especially with porous materials like zeolites or metal-organic frameworks. Studied reactions include selective oxidations, including dehydrogenative couplings via C–H activation, and selective hydrogenations. Recent topics include the upconversion of waste polymers by mild catalytic reactions, and the use of zeolites for combating PFAS pollution. He won a series of prizes, including the BASF Catalysis Award and the IPMI’s Student Advisor’s Award (twice). He is an Associate Editor of the journal Catalysis Science and Technology.

The activation of C–H bonds enables unprecedented step efficiency in the synthesis of C–C bonds linking (hetero)aromatics. In contrast to the conventional Suzuki and related coupling reactions, direct C–C coupling via C–H activation avoids the preparation of at least one aryl halide or arylmetal reactant. Indoles are important synthetic targets in commercial drug compounds, and frequently require the attachment of an aryl moiety (Scheme [1a]). For example, the selective estrogen receptor modulator bazedoxifene consists of a 2-phenylindole core structure.[1] An indole scaffold bearing an aromatic substituent is also present in the molecular structure of HMG-CoA reductase inhibitor fluvastatin, a member of the important cholesterol-lowering statin drugs.[2] A recently FDA-approved anticancer agent is the poly-ADP ribose polymerase-1 inhibitor rucaparib, with an azepino[5,4,3-cd]indole backbone linked to an aromatic residue on its C2 position.[3] Such compounds containing indole-fused azepine rings are occasionally found among the naturally occurring indole alkaloids, and can exhibit promising bio-activity.[4]

Due to their electron-rich nature, indoles have emerged as attractive reactants for Pd(II)-catalyzed C–H activation. A variety of methods are now available for the intermolecular coupling with aryl halides, effectively replacing the conventional organometallic reactants by indoles.[5] Stoichiometric carboxylate or carbonate bases are often used in such ­C–H/­C–X­ couplings, leading to highly regioselective indole arylations at the C2 position.[6] In the current mechanistic understanding, this regioselectivity originates from a ‘concerted metalation-deprotonation’ (CMD) of the more labile C–H bond at the C2 position of indoles.[7] This mechanism combines the electrophilic activation by the Pd(II) metal center with a simultaneous protonation of the carboxylate ligand. Interestingly, the addition of stoichiometric silver salts allows the reaction to proceed at room temperature.[8] Silver ions can abstract halides from the Pd(II) catalyst, eliminating the need for an external base. The C–H arylation of indoles under mild conditions has also been achieved in oxidative coupling reactions, which involve the addition of nucleophilic reagents such as arylboronic acids or trifluoroboronate salts.[9] However, the consumption of stoichiometric metal reagents should be avoided in industrial-scale applications to safeguard the economic appeal and sustainability of the reaction.

While the C–H/C–X couplings of N-substituted indoles using carboxylate or carbonate bases proceed with excellent yields, indoles with a free heterocyclic NH-functionality are generally less effective and show only moderate yields, or no C2-arylated coupled products at all.[6] [10] In the case of catalytic systems based on phosphine ligands, significant formation of the C–N coupled by-product has been observed.[6a,c] The N-substituents on indoles can either protect the electrophilic catalyst from unwanted N-coordination and prevent possible C–N coupling, or increase the reactivity of the heteroaromatic ring with electron-donating substituents (e.g., N-alkylindoles). However, if such N-substitutions are not present in the final product, the step-efficiency of the overall synthetic route is compromised with an additional protection and deprotection step.

Two alternative strategies have been reported that directly aim at the C–H/C–X arylation of indoles with free NH-functionalities. First, a norbornene-mediated Catellani-type coupling has been effective for unprotected indoles, leading to the C2-arylation in high yields.[11] High palladium loadings (10 mol%) were, however, required, which renders these reaction conditions less enticing for pharmaceutical production. A second strategy entails the use of metal additives that can strongly coordinate to the N-heteroatom, after the formation of the corresponding indolyl anion via deprotonation (Scheme [1b]). The negatively charged indole ring becomes significantly more electron-rich and may therefore gain additional reactivity in Pd(II)-catalyzed C–H activation. Sames and co-workers discovered that the formation of indolyl Mg salts with the Grignard reagent MeMgCl promotes the C–H arylation of indoles at their C3 position.[12] Recently, Mohr et al. have found that high catalytic activity could be obtained by generating an indolyllithium reactant with LiHMDS.[13] However, the use of very strong bases limits the functional group tolerance of these coupling reactions. Upon addition of two equivalents of CuI, Bellina et al. reported a base-free C–H arylation of indoles that occurs at the C2 position instead, but modest yields were obtained in spite of high Pd-catalyst loadings.[14]

Several challenges complicate the widespread application of indole C–H activation in organic syntheses. Cross-coupling reactions are ideally planned in the final steps of a synthetic route, to obtain convergent syntheses and limit the required quantities of precious Pd metal. Likewise, the C–H activation should exhibit the functional group tolerance required in these late-stage functionalizations and proceed with excellent yield while using minimal catalyst loadings. In this work, we report on the high-yielding C–H arylation of the 8-fluoroazepino[5,4,3-cd]indol-6-one scaffold as a final, convergent coupling step in the synthesis of the FDA-approved drug rucaparib (Scheme [1c]). In contrast to the conventional synthetic route, which involves the bromination of the azepino[5,4,3-cd]indole scaffold prior to coupling with an arylboronic acid reactant,[15] a step-efficient method was found that directly activates the C–H bond of the indole ring. Based on the addition of co-catalytic Cu-complexes for the N-coordination of indoles, we demonstrate that an effective C–H/C–X coupling of a non-protected, highly functionalized indole scaffold can be obtained without the use of stoichiometric organometal reagents.

Table 1 Discovery and Initial Optimization of 8-Fluoroazepino[5,4,3-cd]indol-6-one C–H Arylation with Phenyl Halides with a Cu-Based Co-Catalyst^a

Entry	Cu additive (equiv)	Base	Aryl halide/triflate	Yield (%)b
1	–	KOAc	PhI	n.d.
2	CuI (2.0)	–	PhI	26
3	CuI (2.0)	KOAc	PhI	66
4	CuI (2.0)	KOAc	PhBr	62
5	CuI (2.0)	KOAc	PhOTf	2
6	CuI (2.0)	KOAc	PhCl	n.d.
7	CuI (0.2)	KOAc	PhBr	56
8	CuI (0.1)	KOAc	PhBr	23
9	CuI (0.1)	KOPropc	PhBr	25
10	CuI (0.1)	KOBzd	PhBr	14
11	CuI (0.1)	KOPiv	PhBr	41
12	CuI (0.1)	K2CO3	PhBr	58
13	CuI (0.1)	CsOAc	PhBr	53
14	CuI (0.1)	CsOPiv	PhBr	75 (68)e
15	CuI (0.1)	Cs2CO3	PhBr	76
16	CuI (0.1)	CsOPiv	PhBr	51f

^a Reaction conditions: Pd₂dba₃ (0.0005 mmol); 8-fluoroazepino[5,4,3-cd]indol-6-one (0.05 mmol), aryl halide (0.1 mmol), base (0.1 mmol), CuI (0–0.1 mmol), DMA (1 mL), 160 °C, 24 h, argon atmosphere.

^b GC yield. n.d.: Not detected.

^c Potassium propionate.

^d Potassium benzoate.

^e Isolated yield.

^f With Pd(OAc)₂ (0.001 mmol, 2 mol%) as Pd-precursor.

To evaluate the potential of indole C–H activation in a convergent synthesis of rucaparib, we explored the strategy of metal N-coordination for the C–H arylation of the 8-fluoroazepino[5,4,3-cd]indol-6-one scaffold with aryl halides (Table [1]). Using 1 mol% of Pd₂dba₃ as catalyst precursor, the cross-coupled product was found after 24 hours at 160 °C when two equivalents of CuI were added to the reaction (Table [1], entries 1 and 2). While a low yield was observed in these base-free conditions, similar to those reported by Bellina et al.,[14] we hypothesized that the addition of a carboxylate base to the catalytic system could help the catalytic cycle turn round, by abstracting the halide and promoting the C–H activation. Indeed, a moderate yield of 66% of the product was obtained with two equivalents of KOAc, along with small fractions (<5% yield) of biarylated side-products (entry 3). The catalytic reaction was also effective with bromobenzene as the coupling partner (entry 4). The yield was, however, drastically decreased when phenyl triflate was used, and no coupling products were detected in the case of chlorobenzene (entries 5 and 6). These results indicate that the oxidative addition of aryl triflates and chlorides on the phosphine-free Pd-catalyst becomes exceedingly difficult. Next, we evaluated the effect of the CuI concentration on the overall reaction yield (Figure [1]). Interestingly, lowering the concentration of Cu(I) below one equivalent did not strongly decrease the yield of cross-coupled products (entries 7 and 8). Even at low concentrations moderate yields were observed, which confirms a co-catalytic role of CuI in the reaction. In addition to 10 mol% of CuI co-catalyst, the reaction was further optimized by screening different stoichiometric bases (entries 9–12). Substitution of KOAc for potassium propionate resulted in a slight increase in reaction yield, whereas a decrease was found in the case of potassium benzoate. The stronger bases potassium pivalate (KOPiv) and potassium carbonate (K₂CO₃) resulted in higher reaction yields. The yields were further increased upon addition of the corresponding cesium salts, indicating that the solubility of the base in DMA is a crucial factor (entries 13–15). The highest reaction yields were obtained with either CsOPiv or Cs₂CO₃ as the base, and no side-products were detected by GC analysis. The use of Pd(OAc)₂ as a Pd(II) precatalyst resulted in a lower reaction yield of 51% (entry 16).

Next, we proceeded with the screening of several other Cu-based co-catalysts in the reaction with 2 equivalents of CsOPiv base (Table [2]). Upon variation of the anionic ligand, a minor decrease in reaction yield was observed when CuI was changed for CuBr (Table [2], entries 2 and 3). The CuOAc complex was also a suitable co-catalyst with intermediate activity (entry 4). The corresponding Cu(II) acetate complex was also effective, which may suggest that the actual active catalytic species is a Cu(II) species originating from the oxidation of Cu(I) (entry 5). In comparison to the anhydrous Cu(OAc)₂, the Cu(OAc)₂·2H₂O complex resulted in a slightly lower yield (entry 6). Other anions on the Cu(II) co-catalyst were also tested, such as acetylacetonate, triflate, and nitrate (entries 7–10). The latter complex resulted in the highest reaction yield of 77% after 24 hours. It is, however, likely that the anions of the Cu pre-catalysts are exchangeable in the presence of stoichiometric pivalate as a bidentate and basic ligand. Other metal nitrate complexes were also tested for catalytic activity. A catalytic quantity of Zn(NO₃)₂·6H₂O resulted in a low yield of 16% (entry 11). In contrast, other metal counter-cations, Li⁺, Mg²⁺, Al³⁺, and Fe³⁺, rendered the catalytic system inactive (entries 12–15).

The effectiveness of the Cu(I) and Cu(II), and to a lesser extent Zn(II), as co-catalysts for the C–H activation of azepinoindoles could originate from the soft deprotonation of the indole N–H bond. The softer nature of these metals and the heterocyclic N-atom results in metal–N bonds with high covalent character, which could stabilize an electron-rich indolyl anion intermediate. It is proposed that this renders the indole substrate more reactive for C–H activation by the electrophilic Pd(II) complex that is generated from Pd(0), after oxidative addition of phenyl bromide and halogen ­abstraction with pivalate. After the C–H activation, sub­sequent reductive elimination could lead to formation of the coupling product.

Table 2 Effect of the Co-Catalyst on the Yield of 2-Phenyl-8-fluoroazepino[5,4,3-cd]indol-6-one via C–H/C–X Coupling with Phenyl Bromide^a

Entry	Co-catalyst (equiv)	Yield (%)b
1	–	n.d.
2	CuI (0.1)	75
3	CuBr (0.1)	71
4	CuOAc (0.1)	67
5	Cu(OAc)2 (0.1)	75
6	Cu(OAc)2·H2O (0.1)	69
7	Cu(acac)2 (0.1)	74
8	Cu(OTf)2(0.1)	64
9	Cu(NO3)2·3H2O (0.1)	77
10	Cu(NO3)2·3H2O (0.05)	65
11	Zn(NO3)2·6H2O (0.05)	16
12	LiNO3 (0.05)	n.d.
13	Mg(NO3)2·6H2O (0.05)	n.d.
14	Al(NO3)3·9H2O (0.05)	n.d.
15	Fe(NO3)3·9H2O (0.05)	n.d.

^a Reaction conditions: Pd₂dba₃ (0.0005 mmol), 8-fluoroazepino[5,4,3-cd]indol-6-one (0.05 mmol), phenyl bromide (0.1 mmol), base (0.1 mmol), co-catalyst (0.005 or 0.0025 mmol), DMA (1 mL), 160 °C, 24 h, argon atmosphere.

^b GC yield. n.d.: Not detected.

Furthermore, the effect of Cs₂CO₃ and CsOPiv concentration was investigated in the presence of 10 mol% of Cu(NO₃)₂·3H₂O as co-catalyst (Figure [2]). On the one hand, a negative influence of excess Cs₂CO₃ on the reaction yield was found, which may be explained by saturation of the electrophilic Pd-catalyst. On the other hand, increasing the concentration of CsOPiv gives rise to higher yields. Due to the steric hindrance of pivalate anions, over-coordination of Pd may be avoided.

Finally, the potential of the reaction was evaluated in the synthesis of rucaparib. The previously reported process chemistry routes involve the sequential bromination of the 8-fluoroazepino[5,4,3-cd]indol-6-one scaffold and Suzuki coupling with 4-formylphenyl boronic acid (Scheme [2], top).[15] The latter organoboron reactant is generally obtained from the 4-bromobenzaldehyde via a multitude of reaction steps: (de)protection of the aldehyde, synthesis of the corresponding Grignard reagent, and borylation. Moreover, the coupling reaction is followed by a final reductive amination step to yield rucaparib. We have tested the ­C–H/­C–X coupling of the azepinoindole scaffold with 4-bro­mo-N-methylbenzylamine, enabling a truly convergent route with superior step-efficiency (Scheme [2], bottom). The coupling reaction of azepinoindole was performed with slightly increased catalyst loadings, 1.25 mol% Pd₂dba₃, 15 mol% Cu(NO₃)₂·3H₂O, and two equivalents of bromoarene and Cs₂CO₃ in DMA. The coupling product rucaparib was obtained in 90% GC yield (71% isolated) and no side-products were detected by GC analysis.

To conclude, a Pd/Cu-based catalytic system was developed for the regiospecific C–H/C–X coupling of an azepino[5,4,3-cd]indole with aryl bromides, which was effective in the convergent synthesis of rucaparib. It is our aspiration that C–H activation may accelerate the production of related bioactive indole scaffolds in the future.

The experimental section has no title; please leave this line here.

All chemicals were obtained via commercial suppliers and used as received. N,N-Dimethylacetamide (DMA, >99.9%, HPLC grade) was used as the solvent without further drying steps. 8-Fluoro-4,5-dihydro-1H-azepino[5,4,3-cd]indol-6(3H)-one was obtained from Ambeed Inc. 4-Bromo-N-methylbenzylamine (>96.5%) was obtained from Sigma-Aldrich. GC analysis was performed on a Shimadzu GC-2010 Pro equipped with a CP-Sil 5 CB column and flame ionization detector. The NMR spectra were recorded on a Bruker Avance III HD 400 MHz spectrometer. Column chromatography was performed on 70–230 mesh silica 60 (Merck) as the stationary phase. For TLC analysis, silica gel on TLC Al foils with fluorescent indicator (254 nm) was used. HRMS spectra were acquired on a quadrupole orthogonal acceleration time-of-flight mass spectrometer (Synapt G2 HDMS, Waters, Milford, MA, USA). Samples were infused at 3μL/min and spectra were obtained in positive ionization mode with a resolution of 15000 (FWHM) using leucine enkephalin as lock mass.

Arylation of 8-Fluoro-4,5-dihydro-1H-azepino[5,4,3-cd]indol-6-one with Bromobenzene; Typical Procedure (Table [2], entry 10)

In a 10 mL glass vial, 8-fluoro-4,5-dihydro-1H-azepino[5,4,3-cd]indol-6-one (10.21 mg, 0.05 mmol) and CsOPiv (23.4 mg, 0.1 mmol) were weighed under ambient atmosphere. The catalytic quantities of Pd₂dba₃ (0.46 mg, 0.0005 mmol) and Cu(NO₃)₂·3H₂O (1.21 mg, 0.005 mmol) were added to the reaction mixture by means of a stock solution in DMA. DMA was added to obtain a total volume of 1 mL. ­Bromobenzene (10.5 μL, 0.1 mmol) was volumetrically injected into the reaction mixture. A Teflon-coated magnetic stirring bar was inserted in the vial, which was then closed with a septum-covered crimp cap. The reaction mixture was flushed with argon and heated to 160 °C for 24 h. After reaction, the product mixture was cooled down to rt, and 150 µL of the product mixture was sampled and analyzed via GC.

The product peaks on the gas chromatograms were identified using the purified products as reference and the GC yields were quantified after determination of the respective response factors by means of a calibration curve.

8-Fluoro-2-phenyl-4,5-dihydro-1H-azepino[5,4,3-cd]indol-6-one [CAS Reg. No. 1577982-06-9]

8-Fluoro-4,5-dihydro-1H-azepino[5,4,3-cd]indol-6-one (51.1 mg, 0.25 mmol), CsOPiv (117.0 mg, 0.50 mmol), Pd₂dba₃ (2.30 mg, 0.0025 mmol), and Cu(NO₃)₂·3H₂O (6.05 mg, 0.05 mmol) were weighed in a glass vial under ambient atmosphere. DMA was added to obtain a total volume of 5 mL. Bromobenzene (52.5 μL, 0.50 mmol) was volumetrically injected into the reaction mixture. The reaction proceeded at 160 °C under magnetic stirring. After 24 h, the resulting product mixture was quenched with sat. aq NaHCO₃ (50 mL), followed by extraction with EtOAc (3 × 50 mL). The crude product mixture was dried (anhyd Na₂SO₄) and filtered. The solvent was evaporated prior to separation via column chromatography (EtOAc–heptane 70:30, R_f = 0.3); yield: 47.9 mg (68%); slightly beige solid; mp 201–203 °C; R_f = 0.3 (hexanes–EtOAc 30:70).

IR (KBr): 3184, 3043, 2921, 1649, 1599, 1502, 1413, 1361, 1209, 1105, 696, 437 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 2.99 (m, 2 H, CH₂), 3.47 (m, 2 H, CH₂), 7.43 (quint, J = 4 Hz, 1 H), 7.51 (dd, J = 24, 4 Hz, 1 H), 7.53 (dd, J = 24, 4 Hz, 1 H), 7.59 (m, 3 H), 7.63 (m, 1 H), 8.33 (t, J = 5.8 Hz, 1 H, CONH).

¹³C NMR (400 MHz, DMSO-d ₆): δ = 28.2, 42.1, 100.6, 100.7, 110.9, 111.2, 117.2, 123.6, 127.3, 127.4, 130.4, 136.3, 136.4, 138.8, 158.2, 160.6, 168.3.

¹⁹F NMR (400 MHz, DMSO-d ₆): δ = –119.8.

MS (ES+): m/z (%) = 157.1 (7), 169.0 (15), 209.1 (100), 281.1 (77).

HRMS: m/z [M + H]⁺ calcd for C₁₇H₁₄FN₂O: 281.1090; found: 281.1086

8-Fluoro-2-{4-[(methylamino)methyl]phenyl}-4,5-dihydro-1H-azepino[5,4,3-cd]indol-6-one (Rucaparib) (Scheme [2]) [CAS Reg. No. 283173-50-2]

8-Fluoro-4,5-dihydro-1H-azepino[5,4,3-cd]indol-6-one (51.1 mg, 0.25 mmol), Cs₂CO₃ (162.9 mg, 0.50 mmol), Pd₂dba₃ (2.88 mg, 0.0032 mmol), and Cu(NO₃)₂·3H₂O (9.08 mg, 0.075 mmol) was weighed in a glass vial under ambient atmosphere. DMA was added to obtain a total volume of 5 mL. 4-Bromo-N-methylbenzylamine (100.0 μL, 0.50 mmol) was volumetrically injected into the reaction mixture. The reaction proceeded at 160 °C under magnetic stirring. After 24 h, the resulting product mixture was quenched with sat. aq NaHCO₃ (50 mL), followed by extraction with EtOAc (3 × 50 mL). The crude product mixture was dried (anhyd Na₂SO₄) and filtered. The solvent was evaporated, and the product was purified via column chromatography (DCM–MeOH 95:5, R_f = 0.4). The silica gel column was eluted with 1 vol% of TEA prior to the separation; yield: 57.3 mg (71%); whitish solid; mp 171–173 °C; R_f = 0.4 (DCM–MeOH 95:5).

IR (KBr): 3460, 3176, 3033, 2423, 1651, 1606, 1516, 1466, 1412, 1350, 1209, 1105, 787, 609 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 2.31 (s, 3 H, CH₃), 2.99 (m, 2 H, CH₂), 3.46 (m, 2 H, CH₂), 3.73 (s, 2 H, CH₂), 7.44–7.56 (m, 5 H), 7.61 (s, 1 H), 8.33 (t, J = 5.8 Hz, 1 H, CONH).

¹³C NMR (400 MHz, DMSO-d ₆): δ = 28.2, 36.1, 42.1, 54.9, 100.7, 100.9, 110.9, 111.1, 117.0, 123.5, 124.0, 127.5, 129.9, 130.6, 136.3, 137.3, 158.2, 160.4, 168.3.

¹⁹F NMR (400 MHz, DMSO-d ₆): δ = –119.9.

MS (ES+): m/z (%) = 293.1 (100), 324.2 (23).

HRMS: m/z [M + H]⁺ calcd for C₁₉H₁₉FN₃O: 324.1512; found: 324.1504.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

We are thankful to Prof. Jef Rozenski of the REGA institute at KU Leuven for the acquisition of the HRMS spectra. We also thank Carlos Marquez Admade for his assistance in the IR spectroscopy analysis of the synthesized compounds, and Brent Daelemans for his contribution to the determination of the melting points.

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Corresponding Author

Publication History

Received: 06 July 2021

Accepted after revision: 06 August 2021

Article published online:
17 September 2021

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