Accessing 4-Oxy-Substituted Isoquinolinones via C–H Activation and Regioselective Migratory Insertion with Electronically Biased Ynol Ethers

Abstract

The Rhodium-catalyzed C–H activation and annulation with ynol ethers to directly provide 4-oxy substituted isoquinolinones is reported. The polarized nature of ynol ethers provides an electronic bias for controlling the regioselectivity of the migratory insertion process. While the highly reactive nature of ynol ethers presents a challenge, mild conditions were found to provide product in moderate to good yield. Utility was demonstrated by application in the synthesis of a prolyl-4-hydroxylase inhibitor framework.

Introduction

Throughout the last decade, C–H activation has been a thriving field of organic research yielding new transformations that have the ability to rapidly functionalize relatively simple substrates or to functionalize late stage intermediates.¹ Chelation assisted C–H activation, in particular, is a common strategy that has facilitated a rapid assembly of biologically relevant frameworks such as isoquinoline, isoquinolinone, pyridine, and other N-containing scaffolds.² In the context of these N-containing heterocycles, Guimond and Fagnou³ as well as Satoh, Miura and coworkers⁴ built upon the work of Jones and coworkers⁵ to contemporaneously develop Rh^III-catalyzed oxidative cyclizations preparing isoquinolines via C–H activation of imine substrates and annulation with disubstituted alkynes. Following this early work with imines, Rovis and coworkers demonstrated the competence of benzamides as coupling partners in the synthesis of isoquinolinones with the use of an external oxidant to turn over the Rh^III catalyst in 2010 (figure 1).⁶ Fagnou and coworkers expanded upon this work in 2010, and developed a catalytic system that utilized an internal oxidant in the N-methoxy group, and afforded isoquinolinones in excellent yields.⁷ Fagnou later found in 2011 that by changing the internal oxidant they could retain the efficacy of isoquinolinone synthesis while reducing catalyst loading, and reacting at ambient temperature.⁸ Recently, more readily available metals, such as cobalt⁹ and ruthenium¹⁰, have been used as catalysts.

Figure 1.

Previous work synthesizing isoquinolinones via Rh^III catalyzed C-H activation.

Application of these technologies to target-directed syntheses, such as the synthesis of biologically active species, would be facilitated by methods that deliver products with predictable regioselectivity and manipulable handles. There are a few general preferences that are observed depending on the nature of the alkyne substituents (figure 2a): (1) If R₁ is aryl and R₂ is alkyl, then the aryl group is observed proximal to the nitrogen; (2) if both R₁ and R₂ are alkyl, then the more sterically demanding group is observed distal to the nitrogen; (3) terminal alkynes, when tolerated, provide products with substitution proximal to the nitrogen. Good selectivity is observed from the benzamide/benzhydroxamic acid substrates; though mixtures of regioisomeric products are observed from more challenging substrates, such as acrylamides and related substrates.¹¹ Predictable annulation products with potential for further manipulation remains a challenge.

Figure 2.

a) General selectivity guidelines for regioselective annulations; b) polarization of ynol ethers; c) thermal rearrangement to ketenes; d) limited examples of migratory insertion with ynol ethers; and e) synthesis of 4-oxy isoquinolinones.

As part of our efforts to prepare the biologically active 4-oxy substituted isoquinoline framework,¹³ we hypothesized that highly polarized ynol ethers (figure 2b) could override other selectivity biases to provide a single cyclization product and address a key limitation in current C–H activation/annulation methodology by providing heteroatom functionalization of the 4-position. Indeed, You and co-workers observed 4-aminoisoquinolone derivatives from the cyclization of N-methylbenzamides and ynesulfonamides.¹⁴ While most alkyne substrates had an aryl group, reinforcing the generally observed pattern of product isomers, ynesulfonamides bearing alkyl groups including a bulky tBu group delivered the 4-amino products with no reported regioisomer products. Owing to the success of ynesulfonamides in C–H activated isoquinolinone synthesis, we were optimistic that ynol ethers would provide a similar selectivity profile.

In contrast to their amino cousins bearing acyl or sulfonyl groups to attenuate polarization of the triple bond, ynol ethers are generally less stable and more difficult to handle.¹⁵ In fact, much of the reported chemistry of ynol ethers takes advantage of a relatively facile thermal isomerization to ketenes via a hydride shift from the alkyl side of ynol ethers (figure 2c).¹⁶ Further, there are relatively limited examples of ynol ethers participating as migratory insertion substrates. Palladium catalyzed hydroarylation and hydroalkenylation reported by Zhu and coworkers is a notable exception to this (figure 2d).¹⁷ We hypothesized that ynol ethers could undergo selective migratory insertion due to the polarized nature of the alkyne. Herein we report the highly regioselective synthesis of isoquinolinones using electronically biased ynol ethers (figure 2e).

Results and Discussion

Our efforts began utilizing N-pivaloyloxy benzamide 1a and 1-phenoxyhexyne 2a as our model substrates. Initial reaction conditions of 2.5 mol% [Cp*RhCl₂]₂ and 25 mol% NaOAc in 1,2-dichloroethane provided isoquinolinone 3aa in a 55% yield after 4 hours. As preliminary studies indicated potential degradation of the ynol ether substrate, 1.2 equivalents of 1-phenoxyhexyne 2a was added in three equal aliquots (table 1, entry 1) or via syringe pump addition of ynol ether solution. Evaluation of other solvents did not lead to significant increases in yield. However, methanol provided 3aa in acceptable 42% yield, which has proven useful for polar substrates (entry 2). Upon screening a range of additives (entries 3–6) the yield using 1,2-dichloroethane as the solvent could be improved to 82% with the use of tetrabutylammonium acetate (entry 6). Using these conditions, slow or batch-wise addition was no longer found to be necessary and when 2a was added in a single addition a 94% yield was observed (entry 7). Variations in temperature (entries 8–9) and additive loadings (entry 10) did not provide improved product yields. Under the optimized conditions starting material was consumed after 2.5 hours (entry 11). It should be noted that no ketene side products or products derived from interception of ketene side products was observed.

Table 1.

Optimization of Reaction Conditions.

Entry	Solvent	Additive	Temp. (°C)	% yielda
1	DCE	NaOAc	30	55
2	MeOH	NaOAc	30	42
3	DCE	CsOAc	30	57
4	DCE	NaOPiv	30	45
5	DCE	NH4OAc	30	76
6	DCE	Bu4NOAc	30	82
7 b	DCE	Bu4NOAc	30	94
8	DCE	Bu4NOAc	45	57
9	DCE	Bu4NOAc	75	trace
10	DCE	Bu4NOAcc	30	79
11 d	DCE	Bu4NOAc	30	96

^a% yield determined by 1H NMR referenced to 2,4,5-trichloropyrimidine as an internal standard.

^bSingle addition of 2a.

^c50 mol% Bu₄NOAc.

^dReaction time was reduce to 2.5 h. For a more extensive optimization table see SI.

With general reaction conditions set, a variety of ynol ethers were evaluated (table 2). While there are a number of methods for preparing ynol ethers, in our hands the most reliable methods were preparation either from an alkoxide and trichloroethylene or from the acetal of chloroacetaldehyde corresponding to the desired alkyl ether partner. In general aryl and alkyl groups were compatible as ynol ether substituents and our optimization substrate provided 3aa in 85% isolated yield. Of note, a neopentyl group lacks the β-hydrogens necessary for rearrangement to a ketene and provided 3ab in 71% yield. The installation of a terminal trimethylsilyl group on the ynol-ether was well tolerated (3ae) and is useful as a terminal alkyne surrogate or a handle for further modification via reactions such as a Fleming-Tamao oxidation¹⁸ or a Hiyama cross-coupling.¹⁹ Interestingly, a O-silyl ynol ether did not react under these reaction conditions (3af). A free propargylic alcohol was not well-tolerated under the reaction conditions, as rhodium rapidly facilitated a Meyer-Schuster rearrangement to give acrylate products.²⁰ While slow addition could alleviate this competing reaction to some extent (3ag), it was found that protection of the alcohol as an acetate ester combined with slow addition of the ynol ether provided 3ah in 52% yield. The methoxy variant 3ai was afforded in 26% yield under these conditions, but the yield could be increased to 66% yield with NaOAc as the additive.

Table 2.

Scope Evaluation of Various Ynol Ethers

^aIsolated yields are averages of at least 2 separate experiments.

^bYnol ether showed no reaction or degradation.

^c2.5 mol% [Cp*RhCl₂]₂, 25 mol% NaOAc, MeOH, syringe pump addition over 2.5 h, 4 h.

^dYields are reported as NMR yields using 2,4,5-trichloropyrimidine as an internal standard.

^e1.8 mmol scale, 25 mol% NaOAc, MeOH, syringe pump addition over 2.5 h, 4 h total.

Using ynol ether 2b, a variety of electronically disparate N-pivaloxybenzamide substrates were evaluated (table 3). The annulation reaction with ynol ethers appears to have a significant dependence on the electronic nature of the arene ring with a 4-OMe substituent providing a poor 11% yield of 3bb, while electron neutral and electron poor substrates generally provided moderate to good yields (3cb-3gb). Interestingly heterocyclic substrate 3hb did not provide product, while the isomeric 3ib was isolated in 74% yield. The discrepancy in yields for these benzamide derivatives likely stems from attenuation of the rate or equilibrium position of the C-H activation process.

Table 3.

Scope Evaluation of Various Benzamides

^aIsolated yields are averages of at least 2 separate experiments, 0.25 mmol scale.

The success of propargylic acetate ynol-ethers as substrates in a one-step synthesis of a highly functionalized isoquinolinone offered a unique opportunity to demonstrate a direct route towards the synthesis of a class of biologically active isoquinolines. These isoquinolines have inhibitory activity against prolyl-4-hydroxylase domain (PHD) enzymes, which play a key role in the regulation of hypoxia inducible factor.¹³ Inhibition of this enzyme is potentially therapeutic in the treatment of chronic kidney disease, cancer-associated anemia, and inflammatory bowel diseases. Utilizing our annulation with an appropriate ynol ether would allow for the direct installation of the requisite 4-oxy functionality and potentially provide a route with opportunity for late stage modifications.

We began the synthesis with the rhodium-catalyzed annulation to provide 3ai in a 66% yield (scheme 1). POCl₃ was used to chlorinate the carbonyl and convert to the isoquinoline 4 in 50% yield. Notably 1-halo isoquinolines can be further functionalized via cross-coupling if desired.²¹ Next, basic methanol hydrolyzed the acetate and the resulting primary alcohol was oxidized to aldehyde 5 in a 63% yield over two steps without purification of the intermediate alcohol. Further oxidation to the carboxylic acid 6 in 84% yield was followed by amide coupling with glycine tert-butyl ester, which provided isoquinoline 7 in an 88% yield. Palladium on carbon and ammonium formate were used to hydrogenate the 1-position of the ring quantitatively.²² A LiCl-TsOH tandem brought about both demethylation of the aromatic methoxy group²³ and hydrolysis of the tBu ester to afford the desired isoquinoline in 86% yield with the correct functionalization at the 3- and 4-positions. In just eight steps, compound 8 was isolated in 15% overall yield with minimal optimization of conditions.

Scheme 1.

Synthesis of Prolyl-4-hydroxylase Domain Inhibitors

Conclusions

In conclusion, ynol ethers have been demonstrated as viable annulation partners in rhodium catalyzed C–H activation reactions to provide isoquinolinone products as single isomers in moderate to good yields. The polarized nature of the ynol ether is presumed to provide the controlling element for selectivity during the migratory insertion step as none of the other insertion isomer has been observed. Finally, this approach was demonstrated to enable the rapid assembly of PHD inhibitors. Current efforts are focused on evaluating ynol ethers in other alkyne difunctionalization reactions.

Experimental

General procedure for the Synthesis of Isoquinolinones (3)

To a round bottom flask 1a (0.25 mol), cyclopentadienyl rhodium chloride dimer (1.25 – 2.5 mol%), and Bu₄NOAc (25 mol%) were added. The flask was evacuated and refilled with N₂ gas. 1,2-Dichloroethane (1.0 mL) was added to the flask, and the mixture was heated to 30 °C. Then, a solution of ynol ether (0.30 mmol) in 1,2-dichlorethane (1.0 mL) was added via syringe. The reaction mixture was then stirred for 2.5 h. The reaction mixture was concentrated, loaded directly onto silica and purified by flash chromatography (CH₂Cl₂/MeOH). Products were verified by ¹H, and ¹³C-NMR. Isolated yields are reported below.

3-butyl-4phenoxyisoquinoline-1(2H)-one (3aa)

This compound was prepared according to the general procedure. Molecular formula: C₁₉H₁₉NO_2. Yellow solid, 62.9 mg and 60.1 mg (85% yield). ¹H NMR (500 MHz, Chloroform-d) δ 11.90 (s, 1H), 8.45 (d, J = 8.0 Hz, 1H), 7.62 (dd, J = 8.1, 7.0, 1H), 7.55 (d,J = 7.7 Hz, 1H), 7.50 (dd, J = 8.2, 7.0 Hz, 1H), 7.29 (dd, J = 8.9, 7.4 Hz, 2H), 7.04 (dd, J = 7.4, 7.4 Hz, 1H), 6.96 (d, J = 7.8 Hz, 2H), 2.69 (t, J = 7.8 Hz, 2H), 1.74 (tt, J = 7.8, 7.4 Hz, 2H), 1.43 (qt, J = 7.4, 7.4 Hz, 2H), 0.94 (t, J = 7.4 Hz, 3H); ¹³C NMR (126 MHz, Chloroform-d) δ 163.6, 158.8, 134.9, 134.7, 132.7, 130.2, 129.7, 127.7, 126.3, 125.0, 122.0, 121.5, 114.9, 30.2, 27.7, 22.4, 13.7; HRMS (ESI): 292.1338 m/z [M]⁻ calculated for C₁₉H₁₈NO₂⁻, 292.1346 m/z observed.

3-buytyl-4-neopentoxyisoquin-1(2H)-one (3ab)

This compound was prepared according to the general procedure. Molecular formula: C₁₈H₂₅NO₂. Yellow solid, 54.0 mg and 48.0 mg (71%). ¹H NMR (500 MHz, Chloroform-d) δ 11.87 (s, 1H), 8.43 (d, J = 8.0, 1H), 7.79 (d, J = 8.0, 1H), 7.72 (dd, J = 8.0, 7.0, 1H), 7.49 (dd, J = 8.0, 7.0, 1H), 3.54 (s, 2H), 2.76 (t, J = 7.4 Hz, 2H), 1.80 (m, 2H), 1.51 (m, 2H), 1.18 (s, 9H), 1.01 (t, J = 7.4 Hz, 3H); ¹³C NMR (126 MHz, Chloroform-d) δ 163.3, 135.3, 134.6, 133.6, 132.3, 127.8, 125.8, 125.0, 120.8, 84.2, 32.5, 30.8, 27.4, 26.7, 22.7, 13.8; HRMS (ESI): 286.1807 m/z [M]⁻ calc’d for C₁₈H₂₄NO₂⁻, 286.1811 m/z observed.

3-methyl-4(neopentyloxy)isoquinolin-1(2H)-one (3ac)

This compound was prepared according to the general procedure. Molecular formula: C₁₅H₁₉NO₂. Yellow solid, 20.2 mg and 21.0 mg (34%). ¹H NMR (500 MHz, Chloroform-d) δ 11.33 (s, 1H), 8.43 (d, 7.7 Hz, 1H), 7.78 (dd, J = 8.3, 1.4 Hz, 1H), 7.72 (ddd, J = 8.3, 7.0, 1.4 Hz, 1H), 7.49 (ddd, J = 8.1, 7.0, 1.2 Hz, 1H), 3.52 (s, 2H), 2.42 (s, 3H), 1.18 (s, 8H); ¹³C NMR (126 MHz, Chloroform-d) δ 163.1, 135.3, 134.9, 132.5, 129.0, 127.8, 125.9, 124.8, 120.6, 83.6, 32.5, 26.7, 13.6; HRMS (ESI): 246.1494 m/z [M+H]⁺ calc’d for C₁₅H₂₀NO₂⁺, 246.1497 m/z observed.

3-butyl-4isobutoxyisoquinolin-1(2H)-one (3ad)

This compound was prepared according to the general procedure. Molecular formula: C₁₇H₂₃NO₂. Yellow solid, 49.4 mg and 47.8 mg mg (71%). ¹H NMR (500 MHz, Chloroform-d) δ 11.67 (s, 1H), 8.42 (d, J = 7.9 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.72 (dd, J = 8.0, 7.3 Hz, 1H), 7.49 (dd, J = 8.0, 7.0 Hz, 1H), 3.65 (d, J = 6.3 Hz, 2H), 2.77 (t, J =7.7 Hz, 2H), 2.2 (m, 1H), 1.79 (m, 2H), 1.5 (m, 2H), 1.2 (d, J = 6.7 Hz, 6H), 1.0 (t, J = 7.4 Hz, 3H); ¹³C NMR (126 MHz, Chloroform-d) δ 162.9, 135.2, 134.9, 133.2, 132.4, 127.8, 125.9, 125.0, 120.9, 81.0, 30.7, 29.3, 27.4, 22.6, 19.4, 13.8; HRMS (ESI): 274.1807 m/z [M+H]⁺ calc’d for C₁₇H₂₄NO₂⁺, 274.1820 m/z observed.

3-(trimethylsilyl)-4-ethoxyisoquinolin-1(2H)-one (3ae)

This compound was prepared according to the general procedure. Molecular formula: C₁₅H₁₉NO₂Si. Yellow solid, 65.4 mg and 60.7 mg (97%). ¹H NMR (500 MHz, Chloroform-d) δ 9.08 (s, 1H), 8.42 (d, J = 8.0 Hz, 1H), 7.71 (m, 2H), 7.53 m, 1H), 3.94 (q, J = 7.0 Hz, 2H), 1.50 (t, J = 7.0 Hz, 3H), 0.44 (s, 9H); ¹³C NMR (126 MHz, Chloroform-d) δ 162.5, 145.4, 134.0, 132.3, 131.7, 128.1, 127.3, 126.7, 121.3, 70.9, 15.4, 1.37; HRMS (ESI): 262.1263 m/z [M+H]⁺ calc’d for C₁₅H₂₀NO₂Si⁺, 262.1260 m/z observed.

3-(hydroxylmethyl)-4-(neopentyloxy)isoquinolin-1(2H)-one (3ag)

To a septum-fitted 1-dram vial 1a (9.0 mg, 0.05 mmol, 1.0 equiv.), cyclopentadienyl rhodium chloride dimer (0.8 mg, 1.25 μmol, 2.5 mol%), and NaOAc (1.0 mg, 12.5 μmol, 25 mol%) were added. The flask was evacuated and refilled with N₂ gas. Methanol (0.2 mL) was added to the flask, and the mixture was heated to 30 °C. A solution of 3-(neopentoxy)prop-2-yn-1-ol (28.4 mg, 0.2 mmol, 4.0 equiv.) in 0.2 mL of methanol was added while heating at 30 °C over 4 hours via syringe pump; bringing the total concentration of the reaction to (0.125 M). The reaction mixture was stirred for 30 minutes after the addition was completed and was concentrated under reduced pressure. An internal standard of 2,4,5-trichloropyrimidine was added (26.2 μmol, 3.0 μL) and the yield was determined by integrating the internal standard in the ¹H-NMR (8.62 ppm) and comparing that to the integrated value for a single proton in the product peak (8.41 ppm). 19% yield.

(4-(neopentyloxy)-1-oxo-1,2-dihydroisoquinolin-3-yl)methyl acetate (3ah)

To a septum-fitted 1-dram vial 1a (9.0 mg, 0.05 mmol, 1.0 equiv.), cyclopentadienyl rhodium chloride dimer (0.8 mg, 1.25 μmol, 2.5 mol%), and NaOAc (1.0 mg, 12.5 μmol, 25 mol%) were added. The flask was evacuated and refilled with N₂ gas. Methanol (0.2 mL) was added to the flask, and the mixture was heated to 30 °C. A solution of 3-(neopentyloxy)prop-2-yn-1-yl acetate (16.8 mg, 0.1 mmol, 2 equiv.) in 0.2 mL of methanol was added while heating at 30 °C over 4 hours via syringe pump; bringing the total concentration of the reaction to (0.125 M). The reaction mixture stirred for 30 minutes after the addition was completed and was concentrated under reduced pressure. An internal standard of 2,4,5-trichloropyrimidine was added (26.2 μmol, 3.0 μL) and the yield was determined by integrating the internal standard in the ¹H-NMR (8.62 ppm) and comparing that to the integrated value for a single proton in the product peak (8.41 ppm). 38% yield.

(4-methoxy-1-oxo-dihydroisoquinolin-3-yl)methyl acetate (3ai)

To a round bottomed flask N-(pivaloxy)benzhydroxamic acid (0.398g, 1.8 mmol, 1.0 equiv.), NaOAc (36.9 mg, 2.1 mmol, 0.25 equiv.), and (Cp*RhCl₂)₂ (11.5 mg, 0.18 mmol, 0.01 equiv.) were added, and the flask was evacuated and refilled with N₂ gas. Methanol (12 mL) was then added to the round bottomed flask. A solution of 3-methoxyprop-2-yn-1-yl acetate (2i) (240 mg, 2.1 mmol, 1.2 equiv.) in 2 mL of methanol was added while heating at 30 °C over 4 hours via syringe pump; bringing the total concentration of the reaction to (0.125 M). The reaction stirred for 30 minutes after the addition was complete and the reaction mixture was concentrated under reduced pressure. The crude product was purified by flash chromatography (Gradient: 2–5% MeOH in CH₂Cl₂, retention time = 9.5 min.). Molecular formula: C₁₃H₁₃NO₄. Pale yellow solid, 0.293 g (1.18 mmol, 66% yield). ¹H NMR (500 MHz, Chloroform-d) δ 9.24 (s, 1H), 8.43 (d, J = 7.9 Hz, 1H) , 7.83 (d, J = 7.9 Hz, 1H, 7.78 (ddd, 7.9, 7.2, 1.0 Hz 1H), 7.58 (ddd, J = 8.1, 7.0, 1.1 Hz, 1H)), 5.21 (s, 2H), 3.91 (s, 3H), 2.19 (s, 3H); ¹³C NMR (126 MHz, Chloroform-d) δ 171.1, 162.5, 138.1, 134.0, 132.7, 128.0, 127.5, 126.4, 126.3, 121.5, 63.1, 58.0, 20.9; HRMS (ESI): 246.0766 m/z [M]⁻ calc’d for C₁₃H₁₂NO₄⁻, 246.0763 m/z observed.

3-butyl-4-neopentoxy-6-methoxyisoquinolin-1(2H)-one (3bb)

This compound was prepared according to the general procedure. Molecular formula: C₁₉H₂₇NO₃. Yellow solid, 11.0 mg and 6.3 mg (11%). ¹H NMR (500 MHz, Chloroform-d) δ 11.4 (s, 1H), 8.31 (d, J = 8.9 Hz, 1H), 7.17 (d, J = 2.4 Hz, 1H), 7.05 (dd, J = 8.9, 2.4 Hz, 1H), 3.93 (s, 3H), 3.52 (s, 2H), 2.72 (t, J = 7.8 Hz, 2H), 1.75 (dd, J = 7.8, 7.5 Hz, 2H), 1.48 (dt, J = 7.4, 7.4 Hz, 2H), 1.18 (s, 9H), 1.00 (t, J = 7.4 Hz, 3H); ¹³C NMR (126 MHz, Chloroform-d) δ 163.2, 162.3, 137.3, 134.3, 133.5, 130.0, 118.65, 115.9, 101.8, 83.8, 55.4, 32.5, 30.6, 27.3, 26.6, 22.5, 13.8; HRMS (ESI): 316.1913m/z [M]⁻ calc’d for C₁₉H₂₆NO₃⁻, 316.1906 m/z observed.

3-butyl-4-neopentoxy-6-bromoisoquinolin-1(2H)-one (3cb)

This compound was prepared according to general procedure. Molecular formula: C₁₈H₂₄NO₂Br. Yellow solid, 60.6 mg and 55.5 mg (64%). ¹H NMR (500 MHz, Chloroform-d) δ 11.21 (s, 1H), 8.24 (d, J = 8.6 Hz, 1H), 7.91 (d, J = 1.9 Hz, 1H), 7.56 (dd, J = 8.6, 1.9 Hz, 1H), 3.50 (s, 2H). 2.72 (t, J = 7.9 Hz, 2H), 1.76 (m, 2H), 1.48 (dt, J = 7.4, 7.4 Hz, 2H), 1.2 (s, 9H), 1.00 (t, J = 7.4 Hz, 3H); ¹³C NMR (126 MHz, Chloroform-d) δ 162.7, 136.7, 135.1, 133.6, 129.6, 129.2, 127.9, 123.7, 123.5, 84.3, 32.6, 30.7, 27.4, 26.6, 22.6, 13.8; HRMS (ESI): 364.0912 m/z [M]⁻ calc’d for C₁₈H₂₃BrO₂⁻, 364.0914 m/z observed.

3-butyl-4-neopentoxy-6-flouroisoquinolin-1(2H)-one (3db)

This compound was prepared according to the general procedure. Molecular formula: C₁₈H₂₄NO₂F. Yellow solid, 44.0 mg and 40.2 mg (56%). ¹H NMR (500 MHz, Chloroform-d) δ 12.03 (s, 1H), 8.42 (dd, J = 8.9, 8.8 Hz, 1H), 7.38 (d, J = 10.0 1H), 7.17 (dd, J = 8.6, 8.4 Hz, 1H), 3.51 (s, 2H), 2.75 (t, J = 7.9 Hz, 2H), 1.80 (m, 2H), 1.51 (m, 2H), 1.17 (s, 9H), 1.01 (t, J = 7.4 Hz, 3H); ¹³C NMR (126 MHz, Chloroform-d) δ 166.6, 164.6, 162.7, 137.8 (d, J = 9.8 Hz), 135.3, 134.1 (d, J = 3.2 Hz), 131.0 (d, J = 10.0 Hz), 121.5, 114.6 (d, J = 24.0 Hz), 106.1 (d, J = 23.3 Hz), 84.1, 32.5, 30.8, 27.4, 22.6, 13.8’ HRMS (ESI): 304.1713 m/z [M]⁻ calc’d for C₁₈H₂₃FO₂⁻, 304.1725 m/z observed.

3-butyl-4-neopentoxy-6-(trifluoromethyl)isoquinolin-1(2H)-one (3eb)

This compound was prepared according to the general procedure. Molecular formula: C₁₉H₂₄NO₂F₃. Yellow solid, 44.9 mg and 46.7 mg (52%). ¹H NMR (500 MHz, Chloroform-d) δ 11.64 (s, 1H), 8.51 (d, J = 8.4 Hz, 1H), 8.08 (s, 1H), 7.67 (d, J = 8.4, 1H), 3.53 (s, 2H), 2.77 (t, J = 7.4 Hz, 2H), 1.80 (tt, J = 7.9, 7.5 Hz, 2H), 1.51 (qt, J = 7.4, 7.4 Hz, 2H), 1.19 (s, 9H), 1.02 (t, J = 7.4 Hz, 3H); ¹³C NMR (126 MHz, Chloroform-d) δ 162.3, 135.3 (d, J = 17.4 Hz), 134.3, 134.2 128.9, 126.9, 124.9, 122.8, 121.9, 118.5, 84.5, 32.6, 30.7, 27.4, 26.6, 22.6, 13.8; HRMS (ESI): 354.1681 m/z [M]⁻ calc’d for C₁₉H₂₃F₃NO₂⁻, 354.1692 m/z observed.

3-butyl-4-neopentoxy-6-nitroisoquinolin-1(2H)-one (3fb)

This compound was prepared according to the general procedure. Molecular formula: C₁₈H₂₄N₂O₄. Yellow solid, 35.3 and 40.5 mg (45%). ¹H NMR (500 MHz, Chloroform-d) δ 10.94 (s, 1H), 8.67 (s, 1H), 8.54 (d, J = 10.4 Hz, 1H), 8.23 (d, J = 8.7 Hz, 1H), 3.5 (s, 2H), 2.77 (t, J = 7.1 Hz, 2H), 1.78 (tt, J = 8.1, 7.1 Hz, , 2H), 1.50 (qt, J = 7.3, 7.1 Hz, 2H), 1.22 (s, 9H), 1.03 (t, J = 7.2 Hz, 3H); ¹³C NMR (126 MHz, Chloroform-d) δ 161.5, 150.7, 136.0, 135.7, 134.3, 130.0, 128.3, 119.6, 117.0, 84.8, 32.6, 30.5, 27.5, 26.6, 22.5, 13.8; HRMS (ESI): 331.1658 m/z [M]⁻ calc’d for C₁₈H₂₃N₂O₄⁻, 331.1658 m/z observed.

3-butyl-4-neopentoxy-6-cyanoisoquinolin-1(2H)-one (3gb)

This compound was prepared according to the general procedure. Molecular formula: C₁₉H₂₄N₂O₂ Yellow solid, 32.0 mg and 32.4 mg (41%). ¹H NMR (500 MHz, Chloroform-d) δ 11.29 (s, 1H), 8.47 (d, J = 8.3 Hz, 1H), 8.06 (s, 1H), 7.67 (d, J = 8.2 Hz, 1H), 3.51 (s, 2H), 2.75(t, J = 7.9 Hz, 2H), 1.77 (tt, J = 7.8, 7.4. Hz, 2H), 1.5 (qt, J = 7.4, 7.4 Hz, 2H), 1.19 (s, 9H), 1.02 (t, J = 7.4 Hz, 3H); ¹³C NMR (126 MHz, Chloroform-d) δ 161.9, 135.7, 135.5, 133.7, 129.0, 127.7, 127.1, 126.1, 118.5, 116.1, 84.7, 32.6, 30.6, 27.5, 26.6, 22.5, 13.8; HRMS (ESI): 311.1760m/z [M]⁻ calc’d for C₁₉H₂₃N₂O₂⁻, 311.1763 m/z observed.

3-butyl-4-(neopentyloxy)-2,6-naphthyridin-1(2H)-one (3ib)

This compound was prepared according to the general procedure. Molecular formula: C₁₇H₂₄N₂O₂. Yellow solid, 61.6 mg and 46.1 mg (74%). ¹H NMR (500 MHz, Chloroform-d) δ 11.90 (s, 1H), 9.23 (s, 1H), 8.70 (d, J = 5.3 Hz, 1H), 8.14 (d, J = 5.3 Hz, 1H), 3.57 (s, 2H), 2.75 (t, J = 7.9 Hz, 2H), 1.78 (tt, J = 7.4, 7.8 Hz, 2H), 1.52 (qt, J = 7.4, 7.4 Hz, 2H), 1.17 (s, 9H), 1.02 (t, J = 7.4 Hz, 3H); ¹³C NMR (126 MHz, Chloroform-d) δ 162.1, 145.6, 145.6, 135.5, 133.5, 129.6, 129.5, 119.7, 84.9, 32.6, 30.7, 27.3, 26.6, 22.6, 13.8; HRMS (ESI): 287.1760 m/z [M]⁻ calc’d for C₁₇H₂₃N₂O₂⁻, 287.1768 m/z observed.

3-butyl-4-neopentoxy-6-methylisoquinolin-1(2H)-one (3jb)

This compound was prepared according to the general procedure. Molecular formula: C₁₉H₂₇NO₂. Yellow solid, 35.1 mg and 45.2 mg (52%). ¹H NMR (500 MHz, Chloroform-d) δ 11.16 (s, 1H), 8.30 (d, J = 8.2 Hz, 1H), 7.55 (s, 1H), 7.29 (d, J = 10.1 Hz, 1H), 3.52 (s, 2H), 2.72 (t, J = 7.9 Hz, 2H), 2.53 (s, 3H), 1.76 (tt, J = 7.8, 7.4Hz, 2H), 1.48 (qt, J = 7.4, 7.4 Hz, 2H), 1.18 (s, 9H), 1.00 (t, J = 7.4 Hz, 3H); ¹³C NMR (126 MHz, Chloroform-d) δ 163.0, 142.8, 135.3, 134.4, 133.4, 127.8, 127.5, 122.8, 120.6, 84.0, 32.6, 30.8, 27.4, 26.7, 22.6, 22.3, 13.8; HRMS (ESI): 300.1964 m/z [M]⁻ calc’d for C₁₉H₂₆NO₂⁻, 300.1973 m/z observed.

1-chloro-3-methylacetate-4-methoxyisoquinoline (4)

To a 250 mL round bottomed flask (4-methoxy-1-oxo-dihydroisoquinolin-3-yl)methyl acetate (220 mg, 0.89 mmol, 1.0 equiv.) and DMF (60 mL) were added. Next, POCl₃ (0.33 mL, 3.6 mmol, 4.0 equiv.) was added at room temperature, and the reaction mixture was heated 110 °C for 4 hours. The reaction mixture was cooled to room temperature and then poured over ice water. The aqueous mixture was extracted three times with CH₂Cl₂. The combined organic layer was washed five times with water and dried over anhydrous Na₂SO₄. The organic layer was concentrated under reduced pressure, and was purified by flash chromatography (Gradient: 0–6% MeOH in CH₂Cl₂, retention time = 13.0 min.). Molecular formula: C₁₃H₁₂NO₃Cl. White solid, 0.138 g (0.52 mmol, 50% yield). ¹H NMR (500 MHz, Chloroform-d) δ 11.40 (s, 1H), 8.31 (d, J = 8.4 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.82 (dd, J = 7.8, 7.4 Hz, 1H), 7.72 (dd, J = 7.8, 7.4 Hz, 1H), 5.35 (s, 2H), 4.00 (s, 3H), 2.14 (s, 3H); ¹³C NMR (126 MHz, Chloroform-d) δ 170.8, 150.3, 145.8, 139.3, 133.0, 131.3, 129.0, 128.0, 126.9, 122.1, 63.6, 62.2, 21.0; HRMS (ESI): 288.0403 m/z [M-Na]⁺ calc’d for NaC₁₃H₁₂NO₃Cl⁺, 288.0408 m/z observed.

1-chloro-4-methoxyisoquinolin-3-carbaldehyde (5)

To a 25 mL round bottomed flask 1-chloro-3-methylacetate-4-mehtoxyisoquinoline (131 mg, 0.5 mmol, 1.0 equiv.), K₂CO₃ (170 mg, 1.2 mmol, 2.5 equiv.), and MeOH (7 mL) were added. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with EtOAc, and washed with brine. The organic layer was dried over anhydrous Na₂SO₄. The volatile solvents were evaporated under reduced pressure, and the pale solid was dissolved in CH₂Cl₂ (0.5 M). Activated MnO₂ (424 mg, 2.9 mmol, 10.0 equiv.) was added and the mixture was stirred for 30 min at room temperature. The reaction mixture was filtered through Celite and was rinsed through with MeOH. The volatile solvents were evaporated under reduced pressure and the crude product was purified by flash chromatography (Gradient: 30–100% EtOAc in Hexanes, retention time = 3.5 min.). Molecular formula: C₁₁H₈NO₂Cl. White solid, 68 mg (0.31 mmol, 63% yield). ¹H NMR (500 MHz, Chloroform-d) δ 10.34 (s, 1H), 8.41 (m, 2H), 7.93(m, 2H), 4.20 (s, 3H); ¹³C NMR (126 MHz, Chloroform-d) δ 189.3, 155.5, 146.2, 135.9, 133.4, 131.9, 131.7, 129.9, 127.0, 123.8, 64.8; HRMS (ESI): 244.0141 m/z [M-Na]⁺ calc’d for NaC₁₁H₈NO₂Cl⁺, 244.0145 m/z observed.

1-chloro-4-methoxyisoquinolin-3-carboxylic acid (6)

To a 50 mL round bottomed flask 1-chloro-4-methoxyisoquinoli-3-carbaldehyde (64 mg, 0.29 mmol, 1.0 equiv.), 2-methyl-2-butene (1.45 ml, 0.2 M), and tBuOH (6 ml, 0.05 M) were added. Then, a solution of NaClO₂ (262.2 mg, 2.9 mmol, 10.0 equiv.) and NaH₂PO₄ monohydrate (276 mg, 2.0 mmol, 7.0 equiv.) in H₂O (3.0 ml, 0.1M) was added dropwise over 10 minutes. The mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and the organic layer was washed once with 1 M HCl. The aqueous layer was extracted three times with EtOAc. The organic layers were combined and dried over anhydrous Na₂SO₄, and volatile solvents were removed under reduced pressure. The crude product was purified via flash chromatography (Gradient: 6–16% MeOH in CH₂Cl₂, retention time = 4.5 min). Molecular formula: C₁₁H₈NO₃Cl. White solid, 58 mg (0.24 mmol, 84% yield). Note: This substrate proved difficult to completely purify, and the ¹H-NMR spectra show these minor impurities. ¹H NMR (500 MHz, Chloroform-d) δ 10.43 (s, 1H), 8.38 (m, 2H), 7.92 (m, 2H), 4.20 (s, 3H); ¹³C NMR (126 MHz, Chloroform-d) δ 162.5, 155.4, 144.2, 134.5, 132.3, 131.5, 130.0, 128.9, 126.9, 123.9, 64.0; HRMS (ESI): 236.0114 m/z [M]⁻ calc’d for C₁₁H₇ClNO₃⁻, 236.0119 m/z observed.

tert-butyl 2-(1-chloro-4methoxyisoquinoline-3-carboxamido)acetate (7)

To a 25 mL round bottomed flask1-chloro-4-methoxyisoquinolin-3-carboxylic acid (44.0 mg, 0.19 mmol, 1.0 equiv.), HATU (77.2 mg, 0.20 mmol, 1.1 equiv.), and DMF (4 mL) were added. The mixture was stirred at room temperature for 10 minutes. Then, glycine tertbutyl ester (73.7 mg, 0.56 mmol, 3.0 equiv.) in 2.0 mL of DMF was added bring the total reaction concentration to 0.04 M. The reaction was stirred at room temperature for 20 minutes, then diisopropylethylamine (0.10 mL, 0.54 mmol, 2.9 equiv.) was added. The reaction was stirred overnight under a N₂ atmosphere. The reaction was diluted with CH₂Cl₂, and washed five times with DI water, & once with brine. The organic layer was dried over anhydrous Na₂SO₄ and purified by flash chromatography (Gradient: 5–10% MeOH in CH₂Cl₂, retention time = 4.0 min). Molecular formula: C₁₇H₁₉N₂O₄Cl. White solid, 65.0 mg (0.19 mmol, 100% yield). ¹H NMR (500 MHz, Chloroform-d) δ 8.34 (dd, J = 7.9, 7.8 Hz, 2H), 8.31 (s, 1H), 7.87 (dd, J = 8.3, 7.0, 1.2 Hz, 1H), 7.81 (ddd, J = 8.2, 7.0, 1.5 Hz, 1H), 4.20 (d, J = 5.50 Hz, 3H), 4.16 (s, 3H), 1.53 (s, 9H); ¹³C NMR (126 MHz, Chloroform-d) δ 169.0, 163.1, 153.1, 144.0, 134.6, 132.5, 131.5, 130.3, 129.3, 126.7, 123.5, 82.2, 63.8, 42.1, 28.1; HRMS (ESI): 373.0931 m/z [M+Na]⁺ calc’d for NaC₁₇H₁₉N₂O₄Cl⁺, 373.0950 m/z observed.

2-(5-hydroxyisoquinoline-3carboxamido)acetic acid (8)

(1) To a 25 mL round bottomed flask (1-chloro-4-methoxyisoquinoline-3-carboxamid)acetate (28.5 mg, 0.08 mmol, 1.0 equiv.), Pd/C (8.5 mg, 0.08 mmol, 1.0 equiv.), ammonium formate (7.5 mg, 0.12 mmol, 1.5 equiv.), and EtOAc (10 mL) were added. The reaction mixture was refluxed for 1 hour. The crude mixture was filtered through a silica plug to remove the palladium, and the volatile solvents was evaporated under reduced pressure. The crude product was purified by flash chromatography (Gradient: 25–50% EtOAc in Hexanes, retention time = 8.5 min.) to afford tert-butyl-2-(4-methoxyisoquinoline-3-carboxamido)acetate. Molecular formula: C₁₇H₂₀N₂O₄. White solid, 25.3 mg (0.08 mmol, 100% yield). ¹H NMR (500 MHz, Chloroform-d) δ 9.00 (s, 1H), 8.60 (s, 1H), 8.33 (d, J =8.3 Hz , 1H), 8.04 (d, J = 8.25 Hz, 1H), 7.81 (ddd, J = 8.3, 6.9, 1.3 Hz, 1H), 7.73 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 4.23 (d, J = 5.4 Hz, 2H), 4.16 (s, 3H), 1.53 (s, 9H); ¹³C NMR (126 MHz, Chloroform-d) δ 169.3, 164.4, 153.2, 146.4, 133.8, 132.6, 131.3, 130.7, 129.1, 127.4, 122.8, 82.1, 63.5, 42.1, 28.1; HRMS (ESI): 317.1501 m/z [M+H]⁺ calc’d for C₁₇H₂₁N₂O₄⁺, 317.1501 m/z observed.

(2) To a 10 mL round bottomed flask tert-butyl-2-(4-methoxyisoquinoline-3-carboxamido)acetate (25.3 mg, 0.08 mmol, 1.0 equiv.), p-Toluenesulfonic acid monohydrate (33.9 mg, 0.8 mmol, 10.0 equiv.), LiCl (10.0 equiv.), and N-methyl-2-pyrrolidone (1 mL) were added. The reaction mixture was heated to 180 °C for 1 hour. The reaction was quenched with water, and the aqueous layers was extracted three times with EtOAc. The organic layer was washed once with brine, dried over Na₂SO₄ and the volatile solvents were evaporated under reduced pressure. The crude product was purified by flash column (Gradient: 0–3 % AcOH in EtOAc, retention time = 3.5 min) to yield. Molecular formula: C₁₂H₁₀N₂O₄. White solid, 17 mg (0.07 mmol, 86% yield). The ¹³C NMR spectrum was obtained in Acetone-d₆ due to better solubility, however better ¹H-NMR resolution was obtained in DMSO-d₆. ¹H NMR (500 MHz, DMSO-d₆) δ 12.83 (s, 1H), 9.37 (s, 1H), 8.90 (s, 1H), 8.29 (d, J = 7.9 Hz, 1H), 8.21 (d, J = 7.5 Hz, 1H), 7.89 (m, 2H), 7.13 (br s, 1H), 4.05 (d, J = 6.2 Hz, 2H); ¹³C NMR (126 MHz, Acetone-d₆) δ 209.1, 170.2 169.9, 154.4, 142.3, 131.6, 130.2, 129.9, 127.5, 122.1, 68.4, 40.1; HRMS (ESI): 245.0562 m/z [M]⁻ calc’d for C₁₂H₉N₂O₄⁻

Supplementary Material

Electronic Supplementary Information (ESI) available: Experimental procedures, characterization data, ¹H and ¹³C spectra of all new compounds. See DOI: 10.1039/x0xx00000x