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Synlett 2021; 32(02): 202-206
DOI: 10.1055/s-0040-1706548
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Modern Heterocycle Synthesis and Functionalization

Rhodium(III)-Catalyzed C–H Activation: Annulation of Petrochemical Feedstocks for the Construction of Isoquinolone Scaffolds

Joyann S. Barber 
a   Pfizer Oncology Medicinal Chemistry, 10770 Science Center Drive, San Diego, California 92121, USA
,
Dehuan Kong
b   BioDuro, No. 233 North FuTe Road, WaiGaoQiao Free Trade Zone, Shanghai 200131, P. R. of China
,
Wei Li
b   BioDuro, No. 233 North FuTe Road, WaiGaoQiao Free Trade Zone, Shanghai 200131, P. R. of China
,
Indrawan J. McAlpine 
a   Pfizer Oncology Medicinal Chemistry, 10770 Science Center Drive, San Diego, California 92121, USA
,
Sajiv K. Nair 
a   Pfizer Oncology Medicinal Chemistry, 10770 Science Center Drive, San Diego, California 92121, USA
,
Sylvie K. Sakata
a   Pfizer Oncology Medicinal Chemistry, 10770 Science Center Drive, San Diego, California 92121, USA
,
Nicole Sun
b   BioDuro, No. 233 North FuTe Road, WaiGaoQiao Free Trade Zone, Shanghai 200131, P. R. of China
,
Ryan L. Patman  ∗
a   Pfizer Oncology Medicinal Chemistry, 10770 Science Center Drive, San Diego, California 92121, USA
› Author Affiliations
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This manuscript is dedicated to the memory ofProf. Keith Fagnou in celebration of his impact on the field of heterocycle synthesis and functionalization through metal-catalyzed C–H activation

Abstract

We describe a simple and robust procedure for the Rh(III)-catalyzed [4+2] cycloaddition of feedstock gases enabled through C–H activation. A diverse set of 3,4-dihydroisoquinolones and 3-methylisoquinolones have been prepared in good to excellent yields. The effects of using ethylene and propyne as coupling partners on C–H site selectivity have also been explored with a representative set of substrates and are discussed herein.


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Key words

heterocycle synthesis - medicinal chemistry - rhodium catalysis - C–H activation - C–C bond formation - isoquinolone - feedstocks - annulation

The efficient synthesis of heterocycles and their subsequent functionalization is often the key objective of a well-constructed route-design strategy in the context of a drug discovery program. Early effort spent seeking a unified approach for incorporating structural diversity into a required heterocyclic scaffold inevitably reduces the total number of synthetic enablement steps and thus cycle time for analogue synthesis. Leveraging a ubiquitous monomer set and/or commercially available reagents is an effective tactic to further increase time-savings when exploring vector space for structure-based drug design (SBDD). To illustrate these concepts, our team’s approach to the route design of the tetrahydroisoquinoline (THIQ) motif embedded within our series of carbonucleoside inhibitors of PRMT5 is highlighted (Scheme [1]).[1]

Zoom Image
Scheme 1 Retrosynthetic analysis for constructing the tetrahydroisoquinoline (THIQ) scaffold of PRMT5 inhibitors at Pfizer

Our team was tasked with assembling a diverse set of highly substituted THIQ monomers, which would be introduced to our carbocyclic core via palladium-catalyzed allylic etherification (Scheme [1], eq. A).[2] Traditional approaches to the THIQ scaffold typically rely on electrophilic aromatic substitution to construct the C–C bond framework as embodied by the venerable Pictet–Spengler[3] and Pomeranz–Fritsch[4] reactions (Scheme [1], eq. B). Evaluation of these disconnections from the perspective of maximizing diversity and speed to synthesis revealed that the available monomer collections in each case were going to be prohibitively small to meet our objective.

Modern strategies for heterocycle synthesis utilizing transition-metal-catalyzed C–H activation[5] have emerged and, in our example, provided additional monomer sets for consideration (Scheme [1], eq. C). Here, deconstruction of the THIQ framework revealed the opportunity to exploit amide-directed C–H annulation of π-unsaturated feedstocks under the conditions of Rh(III) catalysis.[6] Furthermore, our required amides would originate from substituted salicylic acids which were also an abundant monomer class available within Pfizer. Thus, implementation of this route was envisioned to provide the greatest flexibility for the incorporation of diversity while maintaining a unified synthetic approach to the THIQ scaffold.

Amide-directed Rh(III)-catalyzed C–H activation reactions en route to isoquinolones were pioneered independently by the Fagnou,[7a] Rovis,[7b] Satoh and Miura,[7c] and Li[7d] laboratories in 2010. Their studies demonstrated that disubstituted alkynes could participate in cycloaddition with aryl benzamides if an oxidizing amide directing group or exogenous oxidant were used to promote catalytic turnover. Subsequently, Fagnou[8a] and Glorius[8b] established that N-(pivaloyloxy)benzamides 1 further improved the reactivity of this transformation, thus enabling terminal alkynes and alkenes to be utilized. Given the importance of these heterocyclic motifs,[9] elegant studies from the synthetic community have further optimized the regio-[10] and stereoselectivity[11] of these reactions. Despite this progress, C–C bond formation with feedstock gases[12] remained largely unexplored and we were driven by the need to regioselectively incorporate small aliphatic groups onto this scaffold to interrogate their effect on lipophilic efficiency[13] within the PRMT5 series and other programs at Pfizer. In previous work from our laboratory,[10c] we reported reaction conditions optimized for the delivery of propene gas in ligand-directed regioselective annulations of diverse O-pivaloyl benzhydroxamic acids to furnish 4-methyl-substituted dihydroisoquinolones (Scheme [2]). In this study, we sought to adapt our conditions for the development of robust procedures for rhodium(III)-catalyzed [4+2] cycloadditions of ethylene (2) and propyne (4) gas.

Zoom Image
Scheme 2 Regioselective rhodium(III)-catalyzed annulation of feedstock gases developed at Pfizer.

A multitude of synthetic approaches have been developed to access the 3,4-dihydroisoquinolin-1-one architecture.[14] To our knowledge, however, amide-directed annulations of ethylene (2) are limited to a few isolated examples.[8] [15] In light of our objectives, we pursued the application of our previously identified conditions for the annulation of propene gas[10c] to the coupling of ethylene (2) with some slight modifications. Notably, we replaced the bulky [CptRhCl2]2 catalyst with the commercially available [Cp*RhCl2]2 catalyst typically employed in transformations of this type. Consequently, the reaction now proceeded efficiently at room temperature wherein consumption of starting material was typically observed after stirring overnight. Specifically, N-(pivaloyloxy)benzamides 1 were subjected to 2.5 mol% [Cp*RhCl2]2 and 2.0 equiv cesium pivalate in trifluoroethanol[16] at room temperature under 1 atm of ethylene (2) to afford 3,4-dihydroisoquinolones 3 (Scheme [3]).[17]

Zoom Image
Scheme 3 O-Pivaloylhydroxamic acid scope for the annulation of ethylene.[17]  a For experimental procedures, see ref. 17. b Regioisomeric ratios (r.r.) were determined by 1H NMR analysis of the crude reaction mixtures, and yields correspond to isolated products.

To explore the scope of these conditions, we found that electron-poor, -neutral, and -rich N-(pivaloyloxy)benz­amides underwent smooth insertion of ethylene (2) delivering 3,4-dihydroisoquinolones 3a–3c in 90–91% yields. Furthermore, p-CO2Me and p-CN substituents were tolerant of the methodology to furnish 3d,e which provide functional handles that could be utilized in subsequent manipulations. Next, we tested the reaction’s tolerance toward introduction of substituents ortho to the carbonyl moiety and were pleased to find that both dihydroisoquinolone 3f and 3g were obtained in high yield. In particular, the extent of success with N-(pivaloyloxy)benzamide 1f was surprising given its diminished reactivity as a substrate for propene insertion in our previous report.[10c] Presumably, this observed increase in reactivity could be due to the reduced steric burden of ethylene’s (2) π-face which serves to promote carbometallation, even in the context of a challenging substrate such as 1f. Lastly, we examined substrates with two aryl C–H bonds that could potentially undergo concerted metalation–deprotonation (CMD)[8a] prior to ethylene (2) insertion. Generally, the most acidic aryl C–H bond is favored for activation when operating under this mechanism. To demonstrate, substrate 1h was subjected to the reaction conditions which furnished product 3h in 8:1 regioselectivity favoring the isomer predicted by this mnemonic. However, bromine substitution proximal to the site of C–H activation, as exemplified by substrate 1i, serves to override this preference. Here, annulation occurs preferentially at the C–H bond distal to bromine furnishing 3i in 3:1 regioselectivity. To further illustrate this effect, 3,4-dihydroisoquinolone 3j was delivered as a single regioisomer highlighting the role steric repulsion can play on C–H site selectivity.

Having demonstrated that a variety of O-pivaloyl benz­hydroxamic acids could perform successfully in the cy­cloaddition of ethylene (2), we turned our attention to the use of propyne (4) gas. Terminal alkynes such as this typically undergo dimerization, i.e. Glaser coupling, during rhodium-catalyzed oxidation cyclization when external oxidants, e.g. copper(II) salts, are deployed.[7b] Fagnou and co-workers discovered that pivaloyl hydroxamic acids could serve as mild directing groups while also playing the role of internal oxidant which allowed this limitation to be overcome.[8a] Notably, terminal alkynes predictably deliver 3-substituted isoquinolones under these reaction conditions. Inspired by this work and the opportunity to access 3-methyl-substituted isoquinolones to complement our approach to 4-methyl-substituted dihydroisoquinolones using propene,[10c] we sought to exploit propyne (4) gas as a coupling partner (Scheme [4]).[18]

Zoom Image
Scheme 4 O-Pivaloylhydroxamic acid scope for the annulation of propyne.[18]  a For experimental procedures, see ref. 18. b Regioisomeric ratios (r.r.) were determined by 1H NMR analysis of the crude reaction mixtures, and yields correspond to isolated products. c Reaction was performed at 40 °C. d Reaction time was 32 h.

Extension of our reaction conditions to N-(pivaloyloxy)benzamides 1 under 1 atm of propyne (4) gas gave rise to 3-methyl-substituted isoquinolones 5.[19] Analogous to couplings with ethylene (2), a variety of electronics were well tolerated on the benzene ring as demonstrated by the formation of 3-methyl isoquinolones 5a–c in 75–93% yields. Functional groups at the acid oxidation level were also well tolerated affording 5d and 5e in 70% and 84% yields, respectively. Evaluation of ortho-fluorinated substrate 1f revealed that propyne (4) insertion was more challenging than we had observed with ethylene (2). However, elevation of the reaction temperature to 40 °C facilitates useful levels of conversion which enabled us to isolate a 39% yield of the desired product 5f. In this same vein, construction of isoquinolone 5g,[19] which bears an ortho-benzyloxy group, required an extended reaction time of 32 h to reach completion. To probe the effect of propyne (4) on C–H site selectivity, we re-examined substrates 1h–j using this feedstock. Comparable to our observations with propene[10c] and ethylene (2), the most deshielded proton[20] undergoes C–H acti­vation delivering 3-methyl isoquinolone 5h with 9:1 regio­selectivity. In contrast to ethylene (2), annulation of propyne (4) with N-(pivaloyloxy)benzamide 1i favors C–C bond formation at the most acidic C–H bond albeit with a modest regiochemical preference for producing 5i. To further underscore the effect of sterically encumbered substituents in this regard, meta-acetyl-substituted 1j was subjected to the reaction conditions with propyne (4) gas. Once again, alkyne insertion into the least congested C–H bond gave rise to isoquinolone 5j as a single regioisomer in this case.

In conclusion, we have developed mild and robust procedures for Rh(III) catalyzed [4+2] cycloaddition of O-pivaloyl hydroxamic acids with ethylene (2) and propyne (4) to assemble isoquinolone scaffolds. Our collective studies highlight the effectiveness of trifluoroethanol as a solvent for the delivery of feedstock gases in reactions of this type. Additionally, we have established that a diverse range of functional groups including halides, trifluoromethyl groups, esters, nitriles, ketones, and protected alcohols are tolerated under these conditions. Given the importance of these heterocyclic motifs to drug discovery, this modern approach to their construction will continue to grow as an indispensable tool for the medicinal chemistry community.


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Acknowledgment

We would like to thank Alex Yanovsky (Pfizer) and Jake Bailey (UCSD) for X-ray structure support and Jason Ewanicki (Pfizer) for NMR support. We also thank Frank Ruebsam (Bioduro), Cyrus Mirsaidi (Bioduro), Jennifer Lafontaine (Pfizer), and Martin Edwards (Pfizer) for their leadership and support of this collaboration.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/s-0040-1706548.
  • Supporting Information

  • References and Notes

  • 1 Kumpf RA, McAlpine IJ, McTigue MA, Patman R, Rui EY, Tatlock JH, Tran-Dubé MB, Wythes MJ. WO2017212385, 2017
  • 2 For a selected review on palladium-catalyzed allylic alkylation with heteroatom nucleophiles, see: Trost BM, Zhang T, Sieber JD. Chem. Sci. 2010;  1: 427
    CrossrefSearch in Google Scholar

      • For recent reviews of the Pictet–Spengler reaction, see:
    • 3a Calcaterra A, Mangiardi L, Monache GD, Quaglio D, Balducci S, Berardozzi S, Iazzetti A, Franzini R, Botta B, Ghirga F. Molecules 2020; 25: 414
      CrossrefPubMedSearch in Google Scholar
    • 3b Gholamzadeh P. In Advances in Heterocyclic Chemistry, Vol. 127. Scriven EF. V, Ramsden CA. Elsevier; Amsterdam: 2019: 153
      Search in Google Scholar
  • 4 Alajarín R, Burgos C. In Modern Heterocyclic Chemistry . Alvarez-Builla J, Vaquero JJ, Barluenga J. Wiley-VCH; Weinheim: 2011: 1527
    CrossrefSearch in Google Scholar
  • 5 Muralirajan K, Cheng C.-H. In Transition Metal-Catalyzed Heterocycle Synthesis via C–H Activation . Wu X.-F. Wiley-VCH; Weinheim: 2016: 117
    CrossrefSearch in Google Scholar
  • 12 For a recent review on the use of feedstock reagents in metal-catalyzed C–C bond formation via reductive C=O coupling, see: Doerksen RS, Meyer CC, Krische MJ. Angew. Chem. Int. Ed. 2019; 58: 14055
    CrossrefPubMedSearch in Google Scholar
  • 14 Kulkarni MR, Gaikwad ND. ChemistrySelect 2020; 5: 8157
    CrossrefSearch in Google Scholar
  • 15 For an isolated example cobalt-catalyzed aminoquinoline-directed annulation of ethylene, see: Grigorjeva L, Daugulis O. Org. Lett. 2014; 16: 4684
    CrossrefPubMedSearch in Google Scholar
  • 16 For a highlight on the advantageous effects of fluorinated alcohol solvents on C–H functionalization reactions, see: Wencel-Delord J, Colobert F. Org. Chem. Front. 2016; 3: 394
    CrossrefSearch in Google Scholar
  • 17 General Procedure for Ethylene (2) Insertion To a vial, equipped with a magnetic stir bar and rubber septum, was added O-pivaloyl benzhydroxamic acid (1, 1.00 mmol, 1.0 equiv), [Cp*RhCl2]2 (0.025 mmol, 2.5 mol%), and CsOPiv (2.00 mmol, 2.0 equiv). The vial was purged with ethylene (2) under dynamic vacuum for 10 s. Then trifluoroethanol (5.0 mL, 0.2 M) was added, and the reaction mixture was sparged with ethylene (2) for 2 min. The vial was stirred under a balloon of ethylene (2; atmospheric pressure) at room temperature for 16–20 h. After 16–20 h, the reaction was filtered using EtOAc, and the filtrate was concentrated under reduced pressure. The crude residue was purified via flash column chromatography to afford dihydroisoquinolones 3. Representative Compound 3g Following the general procedure using 1g (424 mg, 1.00 mmol, 1.0 equiv), purification via flash column chromatography (12 g SiO2, Isco, 0–10% MeOH/DCM) afforded dihydroisoquinolone 3g (335.4 mg, 96% yield) as a white solid. 1H NMR (400 MHz, DMSO-d 6): δ = 7.87 (br s, 1 H), 7.61–7.50 (m, 2 H), 7.45–7.34 (m, 3 H), 7.34–7.26 (m, 1 H), 5.18 (s, 2 H), 3.33–3.28 (m, 2 H), 2.86 (t, J = 6.2 Hz, 2 H). 13C NMR (101 MHz, DMSO-d 6): δ = 161.5 (d, J = 2.2 Hz), 154.7 (d, J = 2.2 Hz), 149.0 (d, J = 236.2 Hz), 136.9, 129.5 (d, J = 19.8 Hz), 128.2, 127.5, 127.0, 119.3 (d, J = 2.2 Hz), 117.3, 111.4 (d, J = 23.5 Hz), 70.6, 38.2, 22.8 (d, J = 2.2 Hz). 19F NMR (376 MHz, DMSO-d 6): δ = –122.1 (s).
  • 18 General Procedure for Propyne (4) Insertion To a vial, equipped with a magnetic stir bar and rubber septum, was added O-pivaloyl benzhydroxamic acid (1, 0.300 mmol, 1.0 equiv), [Cp*RhCl2]2 (0.0075 mmol, 2.5 mol%), and CsOPiv (0.600 mmol, 2.0 equiv). The vial was purged with propyne (4) under dynamic vacuum for 10 s. Then trifluoroethanol (1.5 mL, 0.2 M) was added, and the reaction mixture was sparged with propyne (4) for 2 min. The vial was stirred under a balloon of propyne (4; atmospheric pressure) at room temperature for 16–20 h. The balloon deflated slowly overnight but this did not inhibit the reaction. After 16–20 h, the reaction was transferred to a flask using EtOAc and concentrated under reduced pressure. The crude residue was purified via flash column chromatography to afford isoquinolones 5. Representative Compound 5a Following the general procedure using 1a (86 mg, 0.300 mmol, 1.0 equiv), purification via flash column chromatography (4 g SiO2, Biotage, 0–10% MeOH/DCM) afforded isoquinolone 5a (62 mg, 92% yield) as a white solid. 1H NMR (400 MHz, DMSO-d 6): δ = 11.57 (br s, 1 H), 8.30 (d, J = 8.4 Hz, 1 H), 7.97 (s, 1 H), 7.66 (dd, J = 8.4, 1.6 Hz, 1 H), 6.48 (s, 1 H), 2.24 (s, 3 H). 13C NMR (101 MHz, DMSO-d 6): δ = 161.7, 140.6, 138.4, 132.1 (q, J = 31.7 Hz), 128.1, 126.4, 123.9 (q, J = 272.70 Hz), 122.8 (q, J = 4.12 Hz), 120.9 (q, J = 3.4 Hz), 102.6, 18.8. 19F NMR (376 MHz, DMSO-d 6): δ = –61.6.
  • 19 Small-molecule X-ray crystal structures corroborating the regiochemical assignment of 5b (CCDC 2024479) and 5g (CCDC 2024480) have been obtained and deposited. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
  • 20 Handy ST, Zhang Y. Chem. Commun. 2006; 299
    PubMed

Corresponding Author

Ryan L. Patman
Pfizer Oncology Medicinal Chemistry
10770 Science Center Drive, San Diego, California 92121
USA   

Publication History

Received: 25 August 2020

Accepted after revision: 29 September 2020

Article published online:
05 January 2021

© 2021. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

  • References and Notes

  • 1 Kumpf RA, McAlpine IJ, McTigue MA, Patman R, Rui EY, Tatlock JH, Tran-Dubé MB, Wythes MJ. WO2017212385, 2017
  • 2 For a selected review on palladium-catalyzed allylic alkylation with heteroatom nucleophiles, see: Trost BM, Zhang T, Sieber JD. Chem. Sci. 2010;  1: 427
    CrossrefSearch in Google Scholar

      • For recent reviews of the Pictet–Spengler reaction, see:
    • 3a Calcaterra A, Mangiardi L, Monache GD, Quaglio D, Balducci S, Berardozzi S, Iazzetti A, Franzini R, Botta B, Ghirga F. Molecules 2020; 25: 414
      CrossrefPubMedSearch in Google Scholar
    • 3b Gholamzadeh P. In Advances in Heterocyclic Chemistry, Vol. 127. Scriven EF. V, Ramsden CA. Elsevier; Amsterdam: 2019: 153
      Search in Google Scholar
  • 4 Alajarín R, Burgos C. In Modern Heterocyclic Chemistry . Alvarez-Builla J, Vaquero JJ, Barluenga J. Wiley-VCH; Weinheim: 2011: 1527
    CrossrefSearch in Google Scholar
  • 5 Muralirajan K, Cheng C.-H. In Transition Metal-Catalyzed Heterocycle Synthesis via C–H Activation . Wu X.-F. Wiley-VCH; Weinheim: 2016: 117
    CrossrefSearch in Google Scholar
  • 12 For a recent review on the use of feedstock reagents in metal-catalyzed C–C bond formation via reductive C=O coupling, see: Doerksen RS, Meyer CC, Krische MJ. Angew. Chem. Int. Ed. 2019; 58: 14055
    CrossrefPubMedSearch in Google Scholar
  • 14 Kulkarni MR, Gaikwad ND. ChemistrySelect 2020; 5: 8157
    CrossrefSearch in Google Scholar
  • 15 For an isolated example cobalt-catalyzed aminoquinoline-directed annulation of ethylene, see: Grigorjeva L, Daugulis O. Org. Lett. 2014; 16: 4684
    CrossrefPubMedSearch in Google Scholar
  • 16 For a highlight on the advantageous effects of fluorinated alcohol solvents on C–H functionalization reactions, see: Wencel-Delord J, Colobert F. Org. Chem. Front. 2016; 3: 394
    CrossrefSearch in Google Scholar
  • 17 General Procedure for Ethylene (2) Insertion To a vial, equipped with a magnetic stir bar and rubber septum, was added O-pivaloyl benzhydroxamic acid (1, 1.00 mmol, 1.0 equiv), [Cp*RhCl2]2 (0.025 mmol, 2.5 mol%), and CsOPiv (2.00 mmol, 2.0 equiv). The vial was purged with ethylene (2) under dynamic vacuum for 10 s. Then trifluoroethanol (5.0 mL, 0.2 M) was added, and the reaction mixture was sparged with ethylene (2) for 2 min. The vial was stirred under a balloon of ethylene (2; atmospheric pressure) at room temperature for 16–20 h. After 16–20 h, the reaction was filtered using EtOAc, and the filtrate was concentrated under reduced pressure. The crude residue was purified via flash column chromatography to afford dihydroisoquinolones 3. Representative Compound 3g Following the general procedure using 1g (424 mg, 1.00 mmol, 1.0 equiv), purification via flash column chromatography (12 g SiO2, Isco, 0–10% MeOH/DCM) afforded dihydroisoquinolone 3g (335.4 mg, 96% yield) as a white solid. 1H NMR (400 MHz, DMSO-d 6): δ = 7.87 (br s, 1 H), 7.61–7.50 (m, 2 H), 7.45–7.34 (m, 3 H), 7.34–7.26 (m, 1 H), 5.18 (s, 2 H), 3.33–3.28 (m, 2 H), 2.86 (t, J = 6.2 Hz, 2 H). 13C NMR (101 MHz, DMSO-d 6): δ = 161.5 (d, J = 2.2 Hz), 154.7 (d, J = 2.2 Hz), 149.0 (d, J = 236.2 Hz), 136.9, 129.5 (d, J = 19.8 Hz), 128.2, 127.5, 127.0, 119.3 (d, J = 2.2 Hz), 117.3, 111.4 (d, J = 23.5 Hz), 70.6, 38.2, 22.8 (d, J = 2.2 Hz). 19F NMR (376 MHz, DMSO-d 6): δ = –122.1 (s).
  • 18 General Procedure for Propyne (4) Insertion To a vial, equipped with a magnetic stir bar and rubber septum, was added O-pivaloyl benzhydroxamic acid (1, 0.300 mmol, 1.0 equiv), [Cp*RhCl2]2 (0.0075 mmol, 2.5 mol%), and CsOPiv (0.600 mmol, 2.0 equiv). The vial was purged with propyne (4) under dynamic vacuum for 10 s. Then trifluoroethanol (1.5 mL, 0.2 M) was added, and the reaction mixture was sparged with propyne (4) for 2 min. The vial was stirred under a balloon of propyne (4; atmospheric pressure) at room temperature for 16–20 h. The balloon deflated slowly overnight but this did not inhibit the reaction. After 16–20 h, the reaction was transferred to a flask using EtOAc and concentrated under reduced pressure. The crude residue was purified via flash column chromatography to afford isoquinolones 5. Representative Compound 5a Following the general procedure using 1a (86 mg, 0.300 mmol, 1.0 equiv), purification via flash column chromatography (4 g SiO2, Biotage, 0–10% MeOH/DCM) afforded isoquinolone 5a (62 mg, 92% yield) as a white solid. 1H NMR (400 MHz, DMSO-d 6): δ = 11.57 (br s, 1 H), 8.30 (d, J = 8.4 Hz, 1 H), 7.97 (s, 1 H), 7.66 (dd, J = 8.4, 1.6 Hz, 1 H), 6.48 (s, 1 H), 2.24 (s, 3 H). 13C NMR (101 MHz, DMSO-d 6): δ = 161.7, 140.6, 138.4, 132.1 (q, J = 31.7 Hz), 128.1, 126.4, 123.9 (q, J = 272.70 Hz), 122.8 (q, J = 4.12 Hz), 120.9 (q, J = 3.4 Hz), 102.6, 18.8. 19F NMR (376 MHz, DMSO-d 6): δ = –61.6.
  • 19 Small-molecule X-ray crystal structures corroborating the regiochemical assignment of 5b (CCDC 2024479) and 5g (CCDC 2024480) have been obtained and deposited. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
  • 20 Handy ST, Zhang Y. Chem. Commun. 2006; 299
    PubMed

   Permissions and Reprints All articles of this category
Zoom Image
Scheme 1 Retrosynthetic analysis for constructing the tetrahydroisoquinoline (THIQ) scaffold of PRMT5 inhibitors at Pfizer
Zoom Image
Scheme 2 Regioselective rhodium(III)-catalyzed annulation of feedstock gases developed at Pfizer.
Zoom Image
Scheme 3 O-Pivaloylhydroxamic acid scope for the annulation of ethylene.[17]  a For experimental procedures, see ref. 17. b Regioisomeric ratios (r.r.) were determined by 1H NMR analysis of the crude reaction mixtures, and yields correspond to isolated products.
Zoom Image
Scheme 4 O-Pivaloylhydroxamic acid scope for the annulation of propyne.[18]  a For experimental procedures, see ref. 18. b Regioisomeric ratios (r.r.) were determined by 1H NMR analysis of the crude reaction mixtures, and yields correspond to isolated products. c Reaction was performed at 40 °C. d Reaction time was 32 h.