The Use of Aryl-Substituted Homophthalic Anhydrides in the Castagnoli–Cushman Reaction Provides Access to Novel Tetrahydroisoquinolone Carboxylic Acid Bearing an All-Carbon Quaternary Stereogenic Center

Novel aryl-substituted homophthalic acids were cyclodehydrated to the respective homophthalic anhydrides for use in the Castagnoli–Cushman reaction. With a range of imines, this reaction proceeded smoothly and delivered hitherto undescribed 4-aryl-substituted tetrahydroisoquinolonic acids with remarkable diastereoselectivity, good yields and no need for chromatographic purification. These findings significantly extend the range of cyclic anhydrides employable in the Castagnoli–Cushman reaction and signify access to a novel substitution pattern around the medicinally relevant tetrahydroisoquinolonic acid scaffold.


Introduction
The Castagnoli-Cushman reaction (CCR) [1] is a remarkably versatile [4 + 2]-type cyclocondensation of a-C-H-acidic cyclic anhydrides 1 with imines 2 leading, depending on the specific anhydride employed [2], to skeletally diverse [3] lactams 3 bearing multiple substituents, which in many cases proceeds in diastereoselective fashion. This reaction is multicomponent in nature because the requisite imine can be generated in situ from the respective amine and aldehyde [4], which makes this reaction particularly suitable for generating compound libraries in array format for drug discovery ( Figure 1).

Introduction
The Castagnoli-Cushman reaction (CCR) [1] is a remarkably versatile [4 + 2]-type cyclocondensation of a-C-H-acidic cyclic anhydrides 1 with imines 2 leading, depending on the specific anhydride employed [2], to skeletally diverse [3] lactams 3 bearing multiple substituents, which in many cases proceeds in diastereoselective fashion. This reaction is multicomponent in nature because the requisite imine can be generated in situ from the respective amine and aldehyde [4], which makes this reaction particularly suitable for generating compound libraries in array format for drug discovery ( Figure 1). Considering the fact that the cyclic anhydride (1) for the CCR input primarily controls the skeletal nature of the lactam product 3, involvement of novel anhydrides in the reaction promises to deliver molecular frameworks which are either completely novel [5] or carry unprecedented substitution patterns around known cores. Considering the fact that the cyclic anhydride (1) for the CCR input primarily controls the skeletal nature of the lactam product 3, involvement of novel anhydrides in the reaction promises to deliver molecular frameworks which are either completely novel [5] or carry unprecedented substitution patterns around known cores.
Homophthalic anhydride (HPA) is one of the most popular and most reactive anhydrides used in the CCR. The reaction with HPA delivers tetrahydroisoquinolones (THIQs) with good control of diastereoselectivity [6][7][8]. The THIQ scaffold is of undisputable medicinal relevance, as evidenced by various molecular series possessing diverse biological Homophthalic anhydride (HPA) is one of the most popular and most reactive anhydrides used in the CCR. The reaction with HPA delivers tetrahydroisoquinolones (THIQs) with good control of diastereoselectivity [6][7][8]. The THIQ scaffold is of undisputable medicinal relevance, as evidenced by various molecular series possessing diverse biological activities reported in the literature. These can be exemplified by such compounds as adrenocorticotropic hormone receptor modulator 4 [9], apoptosis regulator 5 [10], trypanocidal cysteine protease inhibitor 6 [11], as well as antimalarial 7 [12] (Figure 2). The peripheral group diversity of HPA has been largely limited to the substitutions in the benzene ring [13], while substitutions at the methylene position remain almost completely unexplored except for methyl- [14,15] and benzyl- [15] substituted variants. We became interested in synthesizing novel HPA versions bearing an aryl group at the methylene linker (8) and exploring them as partners in the CCR. Our interest was fueled by the prospect of obtaining, possibly in diastereoselective manner, densely substituted THIQs 9 where the α-position (position 4 of the THIQ scaffold) of the hitherto undescribed carboxylic acid would be an all-carbon stereogenic center ( Figure 3). Herein, we present the results obtained in the course of pursuing this goal.  The peripheral group diversity of HPA has been largely limited to the substitutions in the benzene ring [13], while substitutions at the methylene position remain almost completely unexplored except for methyl- [14,15] and benzyl- [15] substituted variants. We became interested in synthesizing novel HPA versions bearing an aryl group at the methylene linker (8) and exploring them as partners in the CCR. Our interest was fueled by the prospect of obtaining, possibly in diastereoselective manner, densely substituted THIQs 9 where the α-position (position 4 of the THIQ scaffold) of the hitherto undescribed carboxylic acid would be an all-carbon stereogenic center ( Figure 3). Herein, we present the results obtained in the course of pursuing this goal. activities reported in the literature. These can be exemplified by such compounds nocorticotropic hormone receptor modulator 4 [9], apoptosis regulator 5 [10], t cidal cysteine protease inhibitor 6 [11], as well as antimalarial 7 [12] (Figure 2). The peripheral group diversity of HPA has been largely limited to the subst in the benzene ring [13], while substitutions at the methylene position remain almo pletely unexplored except for methyl- [14,15] and benzyl- [15] substituted varia became interested in synthesizing novel HPA versions bearing an aryl group at th ylene linker (8) and exploring them as partners in the CCR. Our interest was fuele prospect of obtaining, possibly in diastereoselective manner, densely substituted 9 where the α-position (position 4 of the THIQ scaffold) of the hitherto undescri boxylic acid would be an all-carbon stereogenic center ( Figure 3). Herein, we pre results obtained in the course of pursuing this goal.

Results
4-Aryl-substituted homophthalic acids 10 required for the preparation of anhydrides 8 were synthesized from indanones 11. These, in turn, were prepared either by triflic acid-promoted arylation of cinnamic acids 12 [16] or by intramolecular Heck reaction of bromochalcone 13 [17]. The Heck reaction approach was used for the methoxy-substituted substrate because the respective TfOH-promoted arylation, when attempted, led to extensive tar formation. Indanones 11 were condensed with diethyl oxalate using either potassium or lithium tert-butoxide as the base, and the resulting condensation products 14 were oxidized with hydrogen peroxide in basic medium (as described previously [18]) to furnish novel homophthalic acids 10a-f in modest to excellent yields over two steps from indanones 11 (Scheme 1).

Results
4-Aryl-substituted homophthalic acids 10 required for the preparation of anhydrides 8 were synthesized from indanones 11. These, in turn, were prepared either by triflic acidpromoted arylation of cinnamic acids 12 [16] or by intramolecular Heck reaction of bromochalcone 13 [17]. The Heck reaction approach was used for the methoxy-substituted substrate because the respective TfOH-promoted arylation, when attempted, led to extensive tar formation. Indanones 11 were condensed with diethyl oxalate using either potassium or lithium tert-butoxide as the base, and the resulting condensation products 14 were oxidized with hydrogen peroxide in basic medium (as described previously [18]) to furnish novel homophthalic acids 10a-f in modest to excellent yields over two steps from indanones 11 (Scheme 1).

Scheme 1. Synthesis of substituted homophthalic acids 10.
For the prospective employment of homophthalic acids in the CCR, anhydrides 8 were prepared immediately before the reaction using acetic anhydride as the cyclodehydrating agent and were used in the condensation with imines without further purification. For the preparation of anhydrides from homophthalic acids 10a-d, the cyclodehydration was performed at room temperature in dichloromethane. For substrates 10e-f, due to limited solubility in the latter conditions, the same reaction was performed in toluene at 80 ℃.
Although the CCR of HPA can be conducted in a range of different solvents [19], after brief optimization, we found the reaction of anhydride derived from unsubstituted diacid 10b to furnish an optimum 72% yield of THIQ cycloadduct 9a as a single diastereomer after refluxing the reaction partners in acetonitrile over 18 h. The same reaction conducted in refluxing toluene gave lower (66%) yield. Interestingly, the reaction in acetonitrile also proceeded to completion at room temperature but with lower yield (55%) and lower diastereoselectivity (dr 5:1, trans-/cis-). Thus, the conditions involving refluxing acetonitrile were extended to anhydrides 8 of this and other homophthalic acids 10 in combination with various imines prepared from aromatic aldehydes (Scheme 2).

Scheme 1. Synthesis of substituted homophthalic acids 10.
For the prospective employment of homophthalic acids in the CCR, anhydrides 8 were prepared immediately before the reaction using acetic anhydride as the cyclodehydrating agent and were used in the condensation with imines without further purification. For the preparation of anhydrides from homophthalic acids 10a-d, the cyclodehydration was performed at room temperature in dichloromethane. For substrates 10e-f, due to limited solubility in the latter conditions, the same reaction was performed in toluene at 80°C.
Although the CCR of HPA can be conducted in a range of different solvents [19], after brief optimization, we found the reaction of anhydride derived from unsubstituted diacid 10b to furnish an optimum 72% yield of THIQ cycloadduct 9a as a single diastereomer after refluxing the reaction partners in acetonitrile over 18 h. The same reaction conducted in refluxing toluene gave lower (66%) yield. Interestingly, the reaction in acetonitrile also proceeded to completion at room temperature but with lower yield (55%) and lower diastereoselectivity (dr 5:1, trans-/cis-). Thus, the conditions involving refluxing acetonitrile were extended to anhydrides 8 of this and other homophthalic acids 10 in combination with various imines prepared from aromatic aldehydes (Scheme 2).
The yields of 4-aryl-substituted THIQ acids 9a-u were generally good after simple evaporation of acetonitrile and trituration of the crude material with hexane and ether, with no need for chromatographic purification. The reactions were completely diastereoselective throughout except for those yielding products 9q-t. The stereochemical identity of products 9a-u was unequivocally confirmed as being trans with respect to the vicinal aryl groups by single-crystal X-ray analysis of compound 9a (Figure 4, see ESI for details). The substituents in the homophthalic portion did not apparently influence the reaction outcome. The scope of the reaction was also quite broad with respect to the aromatic, aldehyde-derived group tolerating heterocyclic motifs as well as phenyl group with a nitro group. Likewise, the scope of amines, aromatic and aliphatic alike, was also fairly broad. The yields of 4-aryl-substituted THIQ acids 9a-u were generally good after simple evaporation of acetonitrile and trituration of the crude material with hexane and ether, with no need for chromatographic purification. The reactions were completely diastereoselective throughout except for those yielding products 9q-t. The stereochemical identity of products 9a-u was unequivocally confirmed as being trans with respect to the vicinal aryl groups by single-crystal X-ray analysis of compound 9a (Figure 4, see ESI for details). The substituents in the homophthalic portion did not apparently influence the reaction outcome. The scope of the reaction was also quite broad with respect to the aromatic, aldehyde-derived group tolerating heterocyclic motifs as well as phenyl group with a nitro group. Likewise, the scope of amines, aromatic and aliphatic alike, was also fairly broad. Despite our initial expectations of potentially lower reactivity of anhydrides 8 in the CCR due to increased steric bulk compared to HPA, the reactivity of these anhydrides was similar to that of HPA (considering the fact that the reaction also proceeded at room temperature, vide supra). This is in line with the observations by others for methyl-and  Despite our initial expectations of potentially lower reactivity of anhydrides 8 in the CCR due to increased steric bulk compared to HPA, the reactivity of these anhydrides was similar to that of HPA (considering the fact that the reaction also proceeded at room temperature, vide supra). This is in line with the observations by others for methyl-and benzyl-substituted versions of HPA [15].
In addition to dicarboxylic acids 10a-f, we prepared 1,2,3-triazol-1-yl-substituted dicarboxylic acid 15 by copper-catalyzed [3 + 2] azide-alkyne cycloaddition of the known [20] azido-substituted homophthalic diethyl ester 16 and phenylacetylene followed by hydrolysis. Due to solubility issues, the cyclodehydration procedure to anhydride 17 was modified, and the reaction was performed in DMF using dicyclohexylcarbodiimide (DCC) as the cyclodehydrating agent. Anhydride 17 proved to be a competent substrate for the CCR; however, due to low solubility of 17 in acetonitrile, the reaction was conducted in DMF at room temperature. Trans-configured cycloadduct 18 was obtained as a single diastereomer in 50% yield, also with no need for chromatographic purification (Scheme 3). Despite our initial expectations of potentially lower reactivity of anhydrides 8 in the CCR due to increased steric bulk compared to HPA, the reactivity of these anhydrides was similar to that of HPA (considering the fact that the reaction also proceeded at room temperature, vide supra). This is in line with the observations by others for methyl-and benzyl-substituted versions of HPA [15].
In addition to dicarboxylic acids 10a-f, we prepared 1,2,3-triazol-1-yl-substituted dicarboxylic acid 15 by copper-catalyzed [3 + 2] azide-alkyne cycloaddition of the known [20] azido-substituted homophthalic diethyl ester 16 and phenylacetylene followed by hydrolysis. Due to solubility issues, the cyclodehydration procedure to anhydride 17 was modified, and the reaction was performed in DMF using dicyclohexylcarbodiimide (DCC) as the cyclodehydrating agent. Anhydride 17 proved to be a competent substrate for the CCR; however, due to low solubility of 17 in acetonitrile, the reaction was conducted in DMF at room temperature. Trans-configured cycloadduct 18 was obtained as a single diastereomer in 50% yield, also with no need for chromatographic purification (Scheme 3).

Conclusions
We have described the synthesis of novel aryl-substituted homophthalic acids. Their cyclodehydration to the respective homophthalic anhydrides and the Castagnoli-Cushman reaction of the latter with a range of imines resulted in good yields and delivered hitherto undescribed 4-aryl-substituted tetrahydroisoquinolonic acids with remarkable Scheme 3. Preparation and use of 1,2,3-triazol-1-yl-substituted cyclic anhydride 17 in the CCR.

Conclusions
We have described the synthesis of novel aryl-substituted homophthalic acids. Their cyclodehydration to the respective homophthalic anhydrides and the Castagnoli-Cushman reaction of the latter with a range of imines resulted in good yields and delivered hitherto undescribed 4-aryl-substituted tetrahydroisoquinolonic acids with remarkable diastereoselectivity, good yields and no need for chromatographic purification. These products are distinct in that they contain an all-carbon quaternary stereogenic centers in the α-position to the carboxylic acid. The cyclodehydration-Castagnoli-Cushman reaction protocol was found to be also transferrable to a novel 1,2,3-triazol-1-yl-substituted homophthalic acid. These findings significantly extend the range of cyclic anhydrides employable in the Castagnoli-Cushman reaction and signify access to a novel substitution pattern around the medicinally relevant tetrahydroisoquinolonic acid scaffold.

General Information
All reagents were obtained from commercial sources and used without further purification. Acetonitrile, toluene and N,N-dimethylformamide were distilled from suitable drying agents (CaH 2 or P 2 O 5 ) and stored over MS 4Å. Mass spectra were recorded with a Bruker Maxis HRMS-ESI-qTOF spectrometer (Moscow, Russia) (electrospray ionization mode). NMR data were recorded with Bruker Avance 400/500 spectrometer (Moscow, Russia) (400.13 MHz for 1 H, 100.61 MHz and 125.73 MHz for 13 C and 376.50 MHz for 19 F) in DMSO-d 6 and were referenced to residual solvent proton peaks (δH = 2.51 ppm) and solvent carbon peaks (δC = 39.52 ppm). NMR and HRMS spectra are in the Supplementary Material.

Preparation of Arylhomophthalic
Acids 10a-10f: General Procedure 1 Step 1. Condensation of arylindanones with diethyl oxalate Compounds 10a,b,d,e: Corresponding indanone (9.6 mmol, 1 equiv.) and diethyl oxalate (4.2 g, 3.9 mL, 28.8 mmol, 3 equiv.) were dissolved in THF (10 mL, dry) in a roundbottom flask, and to the resulting solution a suspension of t-BuOK (3.23 g, 28.8 mmol, 3 equiv.) in THF (15 mL, dry) at room temperature was added dropwise. Next, the flask was stoppered, and the mixture was heated in a metal heating block at 65 • C for 72 h (conversion was estimated by TLC, using DCM as an eluent). After cooling to room temperature, the solvent was evaporated and the mixture was dissolved in CHCl 3 (30 mL), washed with 3% hydrochloric acid solution (1 × 15 mL), water (1 × 15 mL) and brine (1 × 15 mL), then organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated, and the resulting mixture was used in the next step without purification.
Compounds 10c,f were obtained according to nearly the same procedure (but using t-BuOLi instead of t-BuOK), and the heating was performed for 16h.
Step 2. Oxidation A solution of KOH (3.76 g, 67.2 mmol, 7 equiv.) in water (20 mL) was added to the product of the previous step in a round-bottom flask; the mixture was stirred for 20 min, then H 2 O 2 (30%, 27.2 mL) was added dropwise. The solution was stirred overnight at room temperature, then heated in a metal heating block to 50 • C and stirred for two hours (until the mixture became transparent). Activated charcoal (12 g) (powder−100 particle size (mesh)) was added to the resulting chilled solution and intensively stirred for 15 min. The solution was filtered through zeolite, and a solution of concentrated hydrochloric acid was added to the filtrate at room temperature to reach pH 1. The precipitated acid was extracted into EtOAc (3 × 30 mL). The organic layer was combined, dried over anhydrous sodium sulfate and evaporated. The resulting acids 10a-e did not require further purification. The acid 10f was additionally crystallized from acetonitrile. Yields of compounds 10 were calculated for 2 steps.
Products 9a-c and f-u: Diacid 10a-c,f (50 mg) was mixed with DCM (1 mL, dry.) in a screw-cap vial, after which acetic anhydride (6 equiv.) was added to the suspension and the reaction mixture was stirred overnight at room temperature. Then, the solvent was evaporated in vacuo. The resulting crude anhydride was used in the next step without purification or characterization.
For products 9d,e: Diacid 10c,f (50 mg) was dissolved in toluene (3 mL, dry) in screw-cap vial, after which acetic anhydride (6 equiv.) was added to the suspension and the reaction mixture was stirred overnight at 80 • C in a metal heating box. Then, the solvent was evaporated in vacuo. The resulting crude anhydride was used in the next step without further purification.
Step 2. The Castagnoli-Cushman reaction added with stirring. The reaction mixture was kept at 80 • C overnight in a metal heating block. Then, the solvent was evaporated. Next, the crude product was treated with diethyl ether (1 mL), after which pentane (3 mL) was added and the solid was thoroughly ground. After cooling to −20 • C for 20 min, the liquid was decanted. The resulting solid was dried in vacuo to give pure title compound.
Dr values were calculated from integrals of methine protons ( 1 H NMR spectra) from lactam ring.  13 13