Tandem C(sp³)–H Arylation/Oxidation and Arylation/Allylic Substitution of Isoindolinones

Abstract

Isoindolinones comprise an important class of medicinally active compounds. Herein we report a straightforward functionalization of the isoindolinones with aryl bromides (22 examples) using a Pd(OAc)₂/NIXANTPHOS-based catalyst system. Additionally 3-aryl 3-hydroxy isoindolinone derivatives, which exhibit anti-tumor activity, can be accessed via a tandem reaction. Thus, when the arylation product is exposed to air under basic conditions, in situ oxidation takes place to install the 3-hydroxyl group. Furthermore, a tandem arylation/allylic substitution reaction is advanced in which both the arylation and allylic substitution are catalyzed by the same palladium catalyst. Finally, a tandem arylation/alkylation procedure is presented. These tandem reactions enable the synthesis of a variety of structurally diverse isoindolinone derivatives from common starting materials.

Graphical Abstract

Introduction

Chemoselective functionalization of C–H bonds situated adjacent to nitrogen constitutes an attractive strategy to elaborate amine derivatives, which are found in numerous marketed pharmaceuticals.^[1] One tactic for this approach involves the direct deprotonation of the amino alkyl moiety’s sp³ C–H followed by functionalization.^[2] Because of the low acidity of these C–H’s,^[3] chemists usually resort to a two-step protocol beginning with a low temperature deprotonation of the amine derivative with an organolithium base followed by treatment with an electrophile.^[3] The basic nature of the organolithiums and lithiated intermediates, however, can lead to compatibility issues with substrates and transition metal catalysts.^[4] To circumvent this problem, researchers often rely on an intermediate transmetallation step, usually to zinc or to copper, allowing the successful C–arylation of amine derivatives.^[5]

We envisioned a different strategy to simplify these two-step processes. Our idea involves a reversible deprotonation of amino alkyl C–H’s, followed by catalytic in situ arylation, akin to enolate arylation reactions.^[6] To perform the deprotonation and functionalization in the presence of a catalyst and potentially sensitive functional groups, we surmised that commonly employed strong bases (organolithiums and LDA) that might decompose the catalyst or limit the scope of the reaction, were to be avoided.^[4a] At the outset of our work, and other groups^{[2a, 2b, 2g, 2h]} in this area, we hypothesized that an activating group would be necessary to acidify the amino alkyl C–H’s to the point they could be deprotonated under relatively mild conditions. Thus, we initially employed benzylic amines activated by coordination to electron deficient metal complexes, (η⁶-C₆H₅–CH₂NR₂)Cr(CO)₃ (Scheme 1A).^{[2c, 2d]} Using these substrates, enantioselective arylation reactions could be conducted to synthesize diarylmethylamines with high ee.^[2d] Following the lead of Oshima and co-workers,^[2a] we explored organic activating groups, such as ketimines, in the arylation of 2-azaallyl anions (Scheme 1B).^{[2e, 2f, 2k]} Heteroaryl benzylic amines also exhibit enhanced acidity, facilitating arylation (Scheme 1C).^[2j] We also applied our approach to the arylation of weakly acidic N-Boc benzylic amines and related compounds in the presence of LiN(SiMe₃)₂ and a Pd-based catalyst to afford diarymethylamine derivatives (Scheme 1D).^[2i] These methods allow efficient access to pharmaceutically relevant diarylmethylamine core structures. It is noteworthy that the ligand used in Scheme 1B–D is van Leeuwen’s NIXANTPHOS,^[7] a deprotonatable ligand that forms bimetallic catalysts that exhibit exceptional reactivity.^[8]

Scheme 1.

Prior Approaches to Arylation Adjacent to Nitrogen.

To broaden the scope and synthetic utility of our approach to functionalize amino alkyl C–H’s, we envisioned the arylation of isoindolinones. The isoindolinone moiety is found in several natural products such as lennoxamine,^[9] stachybotrine C,^[10] pestalachloride A,^[11] and taliscanine.^[12] It is also the core structure of biologically active compounds, including as pagoclone,^[13] chlorthalidone^[14] and NU8165.^[15] Isoindolinone derivatives display a wide range of biological activities including antihypertensive,^[16] antipsychotic,^[17] anxiolytic,^[18] antiviral,^[19] antileukemic,^[20] antitumoral,^{[19b, 21]} and anti-inflammatory.^[22] They are also vasodilatory agents.^[23]

Given the widespread utility of isoindolinones, it is not surprising that a variety of methods have been introduced for their synthesis, including several transition metal catalyzed reactions.^[24] Nonetheless, certain classes of isoindolinones remain difficult to efficiently access. These include isoindolinones with quaternary centers or oxidation adjacent to nitrogen. Recent advances include C(sp²)–H functionalization reactions. An elegant approach by Kim and coworkers is acylation of N-isopropyl benzamides with a rhodium-based catalyst (Scheme 2A).^[24j] More recently Zhao circumvented the need for excess silver oxidant using TBHP in a Pd-catalyzed C–H activation/annulation reaction for the preparation of 3-hydroxyl isoindolinones (Scheme 2B).^[24m] The conceptual significance of these works not withstanding, they both have practical drawbacks, including use of 3 equiv of silver and the N–isopropyl group, and excess TBHP and use of hydroxamides as N-protecting groups. Herein, we introduce in situ arylation of isoindolinones adjacent to the nitrogen to provide rapid access to a series of 3-aryl isoindolinones (Scheme 3). This class of compounds is found in the core structure in alkaloids 3.^[25] To access more challenging 3-hydroxy isoindolinones, which exhibit anti-tumor activity, a streamlined tandem arylation/oxidation is advanced (Scheme 3). Finally, arylation/functionalization reactions that enable the rapid one-pot preparation of a wide range of isoindolinones containing quaternary carbons at the C-3 position are presented. Among these, a tandem arylation/allylic substitution reaction is developed in which both steps are promoted by the same palladium catalyst.^[26]

Scheme 2.

Synthesis of 3-Substituted Isoindolinones.

Scheme 3.

Arylation of Isoindolinones and Arylation/Tandem Reactions of This Work.

Results and Discussion

In our experience with deprotonative cross-coupling processes (DCCP) of weakly acidic substrates^{[2c–2f, 2i–2k, 8a, 27]} we have observed that palladium complexes of van Leeuwen’s NIXANTPHOS ligand (see Scheme 1 for structure) display outstanding reactivity toward a wide variety of transformations whereas other ligands are much less effective. Based on these studies, we employed Pd(OAc)₂ (5 mol %) and NIXANTPHOS (7.5 mol %) as catalyst to examined the arylation of N-methyl isoindolinone (1a) with 4-bromotoluene 2a. Reactions were conducted in the presence of six bases [LiOtBu, NaOtBu, KOtBu, LiN(SiMe₃)₂, NaN(SiMe₃)₂ and KN(SiMe₃)₂], using 1,4-dioxane as solvent at 50 °C for 4 h. As illustrated in Table 1 (entries 1–6) the six bases afforded the desired arylation product 3aa in 19–98% assay yield (AY, determined by ¹H NMR spectroscopy of the crude products). The highest yield was afforded with NaN(SiMe₃)₂ (98% AY, entry 5). Decreasing the amount of NaN(SiMe₃)₂ from 2 to 1.5 equivalents provided the product without a significant drop in yield (95% AY and 91% isolated yield, entry 7). Reducing the reaction time from 4 to 3 hours afforded a lower yield of the arylation product (89% AY, entry 8). When the reaction temperature was reduced from 50 ^oC to room temperature, no arylated product was obtained (entry 9). Lower catalyst loadings [2.5 mol % Pd(OAc)₂ and 3.75 mol % NIXANTPHOS] generally resulted in lower yields.

Table 1.

Selected Optimization of Arylation of N-Methylisoindolinone 1a with 4-Bromotoluene 2a.

Entry	Base	1a:2a:base	Solvent	Yield [a] [%]
1	LiOtBu	1:1:2	1,4-dioxane	19
2	NaOtBu	1:1:2	1,4-dioxane	71
3	KOtBu	1:1:2	1,4-dioxane	58
4	LiN(SiMe3)2	1:1:2	1,4-dioxane	79
5	NaN(SiMe3)2	1:1:2	1,4-dioxane	98
6	KN(SiMe3)2	1:1:2	1,4-dioxane	68
7	NaN(SiMe3)2	1:1:1.5	1,4-dioxane	95(91) [b]
8	NaN(SiMe3)2	1:1:1.5	1,4-dioxane	89 [c]
9	NaN(SiMe3)2	1:1:1.5	1,4-dioxane	0 [d]

^[a]Yields determined by ¹H NMR analysis of unpurified reaction mixtures with internal standard CH₂Br₂.

^[b]Isolated yield.

^[c]Reaction time 3 h.

^[d]Reaction at room temperature.

The optimized conditions (Table 1, entry 7) were carried forward to evaluate the substrate scope of the arylation reaction of 2-methylisoindolinone (1a) with various aryl bromides 2 (Table 2). The arylated products were obtained in good yields with bromobenzene and 4-tert-butyl bromobenzene providing 3ab and 3ac both in 90% yield. 3-Bromotoluene was also a good coupling partner, furnishing 3ad in 84% yield. Aryl bromides bearing electron-donating groups, such as 4-N,N-dimethylamino and 4-methoxy resulted in cross-coupling products 3ae and 3af in 92–85% yield. 3-Bromoanisole generated the coupling product 3ag in 81% yield. The cross-coupling reactions with aryl bromides bearing electron-withdrawing 4-fluoro and 4-chloro exhibited good yields of 3ah (75%) and 3ai (72%). 3-Bromobenzotrifluoride provided the arylated product 3aj in 43% yield. Other substrates, such as 2-bromobenzofuran, 2-bromonaphthalene and N-methyl-5-bromoindole, also showed good reactivity, furnishing the products 3ak–3am in 71–85% yield.

Table 2.

DCCP of N-Methylisoindolinone 1a with Various Aryl Bromides 2.

^[a]2 equiv of NaN(SiMe₃)₂ was used.

We next turned our attention to the substrate scope of isoindolinone derivatives with electron-donating 4-bromoanisole and electron-withdrawing 1-bromo-4-chlorobenzene (Table 3). In general, N-ethyl isoindolinone (1b) exhibited good reactivity, affording the corresponding products 3bf and 3bi in 85 and 80% yield, respectively. The N-benzyl isoindolinone 1c furnished the products 3cf and 3ci in 93 and 91% yield. It is noteworthy that in the arylation of N-benzyl isoindolinone (1c) no arylation of the N-benzyl group was observed. The N-methyl 6-methyl derivative (1d) provided coupling products 3df and 3di in 76 and 69% yield, respectively. 6-Chloro-N-methyl isoindolinone (1e) proved to be more challenging, affording the products 3ef and 3ei in 57 and 47% yield, respectively. The origin of the reduced yield is most likely due to the proximity of the chloride to the carbonyl group, which will activate the chloride to oxidative addition. We have previously demonstrated that the (NIXANTPHOS)Pd catalyst can activate aryl chlorides, even at room temperature.^[8a] Unfortunately, N-methyl-5-methoxy-isoindolinone (1f) resulted in low yields using NaN(SiMe₃)₂ under our standard conditions. It was, therefore, necessary to perform additional optimization, which revealed that use of 2 equiv of LiN(SiMe₃)₂ in 1,4-dioxane at 50 °C with 4-bromotoluene led to the product 3fa in 70% yield.

Table 3.

Selected Optimization of Arylation of N-Methylisoindolinone 1a with 4-Bromotoluene 2a.

^[a]2 equiv of LiN(SiMe₃)₂ was used.

Recently, Hardcastle and co-workers^[15] reported that the 3-aryl-3-alkoxyisoindolinone scaffold exhibits promising anti-tumor activity through interaction with MDM2-p53. We therefore set out to develop a one-pot arylation/oxidation approach to access the core structure of 3-aryl-3-hydroxyisoindolinone. We envisioned that conducting our arylation of isoindolinones in the presence of additional base could be followed by exposure of the resulting 3-arylisoindolinone to air.^{[27l, 28]} The excess base was anticipated to deprotonate the isoindolinone product and the resulting anion react with dioxygen in the air to generate the oxidized core.

When the arylation reaction of N-methyl isoindolinone (1a) with 4-bromotoluene (2a) was conducted with 3.0 equiv of NaN(SiMe₃)₂ the arylation proceeded to completion, as determined by TLC. The reaction mixture was then cooled to room temperature and exposed to air for 2 h. Workup and analysis of the reaction products indicated complete conversion of the arylated intermediate to the oxidation product, 3-aryl-3-hydroxy-N-methyl isoindolinone.

Next, a series of tandem arylation/oxidation reactions was performed (Table 4). The cross-coupling of N-methyl isoindolinone (1a) with electron neutral aryl bromides 2a–d followed by air oxidation exhibited good reactivity, generating the products 4aa–4ad in 77–89% yield. Aryl bromides bearing electron-donating and withdrawing groups such as 4-N,N-dimethylamino, 4-methoxy, 3-methoxy, 4-fluoro and 4-chloro resulted in the desired products 4ae–4ai in 61–87% yield. The key core structure in the study by Hardcastle et al.^[15] could be accessed by coupling of the N-benzyl isoindolinone (1c) with 4-chlorobromobenzene followed by oxidation. Using the one-pot procedure, N-benzyl-3-(4-chlorophenyl)-3-hydroxyisoindolinone (4ci) was generated in 71% yield.

Table 4.

DCCP of N-Methylisoindolinone 1a with Various Aryl Bromides 2 and Tandem Oxidation with Air.

^[a]2.0 equiv of LiN(SiMe₃)₂ was used.

To diversify the isoindolinone core structures accessible via one-pot tandem reactions initiated with arylation, we next explored use of various electrophiles. Thus, following the approach in Table 4, the arylation was performed, but instead of adding oxygen, different alkyl halides were injected into the reaction mixtures under nitrogen at room temperature. To our satisfaction we obtained the arylation/alkylation products 5 in moderate to high yields (67–90%, Table 5). Arylation of N-methyl isoindolinone (1a) with 4-bromotoluene in the presence of 3 equiv NaN(SiMe₃)₂ was followed by treatment with methyl iodide to generate the methylated adduct containing a quaternary center (5a) in 80% yield. Similarly, arylation of 1a with 4-tert-butyl bromobenzene using 3 equiv of LiN(SiMe₃)₂ followed by reaction with allyl chloride provided the allylated adduct in 90% yield. Employing the N-methyl-6-methyl isoindolinone (1d) with 2-bromonaphthylene and NaN(SiMe₃)₂ followed by n-butyl iodide furnished the alkylated product in 67% yield. N-Benzyl isoindolinone (1c) was arylated using NaN(SiMe₃)₂ and 4-bromo N,N-dimethylaniline with subsequent treatment with benzyl chloride to give the benzylation product 5d in 78% yield. The successful generation of these compounds via substitution reactions inspired us to consider other methods to functionalize the arylated isoindolinone intermediates, including metal catalyzed processes.

Table 5.

DCCP of Isoindolinones with Aryl Bromides and Tandem Alkylation.

^[a]3.0 equiv of LiN(SiMe₃)₂ was used.

Given that the Pd-based catalyst promotes deprotonative cross-coupling reactions, we envisioned reusing this catalyst in the second step of the tandem reaction. We therefore focused on the Tsuji-Trost reactions using different allylic electrophiles. As such, once the reactions between isoindolinones 1 and aryl bromide 2 reached completion, as judged by TLC, allylic carbonates were added at room temperature. We were surprised to find that the palladium catalyzed allylic substitution was completed in 10 min, as judged by TLC (Table 6). The allyl tert-butyl carbonate furnished the arylation/allylation products 6a, 6b and 6d in moderate to good yields (68–89%, Table 6). The cyclic allylic alcohol derivatives were also good substrates in the arylation/allylation reaction. The tert-butyl cyclohex-2-en-1-yl carbonate provided the product 6c in 95% yield with a diastereomeric ratio of ~2:1 and tert-butyl cyclohept-2-en-1-yl carbonate provided the product 6e in 85% yield with a similar diastereomeric ratio (Table 6).

Table 6.

DCCP of Isoindolinones with Aryl Bromides and Allylation in a One-Pot Procedure.

^[a]2.0 equiv of LiN(SiMe₃)₂ was used.

We examined the scalability of our method by performing the arylation reaction of N-methyl isoindolinone (1a) with bromobezene 2b on a 5 mmol scale in the presence of 2.5 mol % Pd(OAc)₂ and 3.75 mol % of NIXANTPHOS. This procedure afforded the coupling product 3ab in 88% isolated yield (0.98 g, Scheme 4A). We also performed the arylation reaction of 6 mmol N-benzyl isoindolinone (1c) with 4-chloro bromobenzene 2i in the presence of 2.5 mol % Pd(OAc)₂ and 3.75 mol % of NIXANTPHOS followed by air oxidation in a one-pot procedure, which furnished the product 4ci in 78% isolated yield (1.64 g, Scheme 4B). It is noteworthy that both these reactions were conducted with a 1.0: 1.0 ratio of the pronucleophiles (isoindolinone) to aryl bromide, demonstrating the high efficiency of these reactions.

Scheme 4.

Gram scale Cross-Coupling of Isoindolinones.

Conclusions and Outlook

In summary, we have developed the first direct palladium catalyzed C(sp³)-H arylation of substituted isoindolinones with various aryl bromide via a deprotonative cross-coupling process (DCCP). In addition, the arylated products can be further transformed into oxidized, alkylated or allylated products in one-pot procedures in good yields. It is noteworthy that our protocol for the tandem arylation/oxidation allows generation of isoindolinone derivatives that are the key intermediate for the synthesis of promising lead compounds that display interesting antitumor activity.

Experimental Section

General Methods

All reactions were conducted under an inert atmosphere of dry nitrogen. Anhydrous 1,4-dioxane and cyclopentyl methyl ether (CPME) were purchased from Sigma-Aldrich and used without further purification. Dimethoxyethane (DME) dichloromethane, and tetrahydrofuran (THF) were dried through activated alumina columns under nitrogen. Other solvents were commercially available and used as received. Chemicals were purchased from Sigma-Aldrich, Acros, Fisher Scientific or Matrix Scientific and solvents were obtained from Fisher Scientific. Thin-layer chromatography was performed on Whatman precoated silica gel 60 F-254 plates and visualized by ultraviolet light. Silica gel (Silicaflash, P60, 40–63 μm, Silicycle) was used for air-flashed chromatography. NMR spectra were obtained using a Brüker 500 MHz Fourier-transform NMR spectrometer at the University of Pennsylvania NMR facility. ¹H and ¹³C chemical shifts in parts per million (δ) were referenced to internal tetramethylsilane (TMS). The infrared spectra were obtained with KBr plates using a Perkin-Elmer Spectrum 1600 Series spectrometer. High-resolution mass spectrometry (HRMS) data were obtained on a Waters LC-TOF mass spectrometer (model LCT-XE Premier) using chemical ionization (CI) or electrospray ionization (ESI) in positive or negative mode, depending on the analyte. Melting points were determined on a Unimelt Thomas-Hoover melting point apparatus and are uncorrected.

Palladium-Catalyzed C(sp³)-H Arylation of Isoindolinones (Tables 2 and 3)

Preparation of Pd(OAc)₂/NIXANTPHOS Stock Solution

An oven-dried 20 mL vial with a stir bar under a nitrogen atmosphere was charged with Pd(OAc)₂ (22.5 mg, 0.1 mmol), NIXANTPHOS (82.7 mg, 0.15 mmol) and 1,4-dioxane (10 mL). The solution was stirred for 5 min before use. 1.0 mL of the stock solution was used for 0.2 mmol scale reactions

General Procedure for the Arylation of Isoindolinone

An oven-dried microwave vial equipped with a stir bar was charged with isoindolinone (0.20 mmol) and NaN(SiMe₃)₂ (55.0 mg, 0.3 mmol) under a nitrogen atmosphere. The stock solution (1.0 mL) of Pd(OAc)₂ (5.0 mol %) and NIXANTPHOS (7.5 mol %) in 1,4-dioxane was added to the reaction vial. The vial was sealed with a cap and the solution was stirred at room temperature for 5 min. Aryl bromide (0.20 mmol) was added to the solution. Note that solid aryl bromides were added to the reaction vial prior to NaN(SiMe₃)₂. The vial was removed from the glove box, and heated to 50 °C in an oil bath with stirring for 4 h. The sealed vial was cooled to room temperature and stirred for 5 min. Water (3 drops) was added to the vial. The reaction mixture was then diluted with diethyl ether (2 mL) and filtered over a short pad of Celite. The pad was rinsed with additional diethyl ether (5 mL) and the solvent was removed under reduced pressure to yield a viscous oil. The crude material was purified by flash column chromatography.

General Procedure for the tandem Arylation/Oxidation

To an oven-dried microwave vial equipped with a stir bar was charged with isoindolinone (0.20 mmol) and NaN(SiMe₃)₂ (110.0 mg, 0.6 mmol) under a nitrogen atmosphere. The stock solution (1.0 mL) of Pd(OAc)₂ (5.0 mol %) and NIXANTPHOS (7.5 mol %) in 1,4-dioxane was added to the reaction vial. The vial was sealed with a cap and the solution was stirred at room temperature for 5 min. Aryl bromide (0.20 mmol) was added to the solution. Note that solid aryl bromides were added to the reaction vial prior to NaN(SiMe₃)₂. The sealed vial was removed from the glove box and heated to 50 °C in an oil bath with stirring for 4 h. The sealed vial was cooled to room temperature and stirred for 5 min. The vial was opened to air and stirred for 2 h. To the vial was added 3 drops of water and the reaction mixture was diluted with diethyl ether (2 mL) and filtered over a short pad of Celite. The pad was rinsed with additional diethyl ether (5 mL) and the solvent was removed under reduced pressure to yield a viscous oil. The crude material was purified by flash column chromatography.

General Procedure for the Tandem Arylation/Alkylation

To an oven-dried microwave vial equipped with a stir bar was charged with isoindolinone (0.20 mmol) and NaN(SiMe₃)₂ (110.0 mg, 0.6 mmol) under a nitrogen atmosphere. 1.0 mL of the stock solution of Pd(OAc)₂ (5.0 mol %) and NIXANTPHOS (7.5 mol %) in 1,4-dioxane was added to the reaction vial. The vial was sealed with a cap and the solution was stirred at room temperature for 5 min. Aryl bromide (0.20 mmol) was added to the solution. Note that solid aryl bromides were added to the reaction vial prior to NaN(SiMe₃)₂. The vial was removed from the glove box, and heated to 50 °C in an oil bath with stirring for 4 h. The sealed vial was cooled to room temperature and stirred for 5 min. The alkyl halide (0.24 mmol) was taken up by a syringe and added to the reaction vial through the cap. The reaction mixture was stirred for 30 min at room temperature. Next, water (3 drops) was added to the vial. The reaction mixture was diluted with diethyl ether (2 mL) and filtered over a short pad of Celite. The pad was rinsed with additional diethyl ether (5 mL) and the solvent was removed under reduced pressure to yield a viscous oil. The crude material was purified by flash column chromatography.

General Procedure for the Tandem Arylation/Allylic Substitution

To an oven-dried microwave vial equipped with a stir bar was charged with isoindolinone (0.20 mmol) and LiN(SiMe₃)₂ (100.4 mg, 0.6 mmol) or NaN(SiMe₃)₂ (110.0 mg, 0.6 mmol) under a nitrogen atmosphere. The stock solution (1.0 mL) of Pd(OAc)₂ (5.0 mol %) and NIXANTPHOS (7.5 mol %) in 1,4-dioxane added to the reaction vial. The vial was sealed with a cap and the solution was stirred at room temperature for 5 min. Aryl bromide (0.20 mmol) was added to the solution. Note that if the aryl bromide was a solid, it was added to the reaction vial prior to NaN(SiMe₃)₂. The sealed vial was removed from the glove box and heated to 50 °C with stirring in an oil bath for 4 h. The sealed vial was cooled to room temperature and stirred for 5 min. Allyl tert-butyl carbonate (0.24 mmol) was taken up by a syringe and added to the reaction vial through the cap. The reaction mixture was stirred for 10 min. Water (3 drops) was added to the vial. The reaction mixture was diluted with diethyl ether (2 mL) and filtered over a short pad of Celite. The pad was rinsed with additional diethyl ether (5 mL) and the solvent was removed under reduced pressure to yield a viscous oil. The crude material was purified by flash column chromatography.