RhIII-Catalyzed Synthesis of Isoquinolones and 2-Pyridones via Annulation of N-Methoxyamides and Nitroalkenes

Abstract

The Rh(III)-catalyzed synthesis of 4-substituted isoquinolones and 2-pyridones by the annulation of N-methoxyamides and nitroalkenes has been developed. Both aliphatic and aromatic nitroalkenes were effective inputs. Annulations also proceeded for aromatic, alkenyl, and heteroaromatic C–H bond starting materials. Moreover, benzoic acid provided a novel nitrodihydroisocoumarin. The structure and relative stereochemistry of this compound, which is an oil at room temperature, was determined unambiguously by single crystal X-ray diffraction of its inclusion complex with a hydrogen-bonded host framework.

A new approach for the rapid and selective synthesis of 4-substituted isoquinolones and 2-pyridones via a Rh(III)-catalyzed annulation is reported. The reaction has broad scope for both the nitroalkene and C–H bond substrate, allowing for efficient access to these medicinally relevant heterocyclic motifs.

*heterocycles by C-H functionalization

Introduction

Transition metal-catalyzed C–H functionalization is a powerful method for the rapid construction of heterocyclic compounds.^[1] Transition metal-catalyzed annulations to give medicinally relevant isoquinolones have in particular been emphasized, and a number innovative and efficient methods have been developed to prepare 3,4-disubstituted derivatives.^[2] In recent years a number of approaches have also been implemented for accessing 3-monosubstituted derivatives, including couplings with terminal alkynes,^[3] α-haloketones,^[4] sulfoxonium ylides,^[5] and 1,1-disubstituted allenes^[6] (Scheme 1A.I). In contrast, very few methods are available for the preparation of 4-monosubstituted isoquinolones.^[7] Recently, Bolm reported the Rh(III)-catalyzed synthesis of 4-substituted isoquinolones using α-chloroaldehydes (Scheme 1B.I).^[8] To the best of our knowledge this is the only general method for the selective synthesis of 4-substituted isoquinolones via C–H functionalization. Based on the limited commercial availability of α-chloroaldehydes and our recent work using nitroalkenes as electrophiles in Rh(III)-catalyzed reactions, we wondered if nitroalkenes could be used for the selective synthesis of 4-substituted isoquinolones and 2-pyridones.^[9]

Scheme 1.

Transition metal-catalyzed synthesis of monosubstituted isoquinolones by C-H functionalization.

Herein, we report on the Rh(III)-catalyzed annulation of N-methoxyamides and nitroalkenes for the selective synthesis of 4-substituted isoquinolones and 2-pyridones. Branched and unbranched aliphatic nitroalkenes were effective inputs for various aromatic and alkenyl N-methoxyamide C–H functionalization substrates. Moreover, aromatic nitroalkenes provide isoquinolones with 4-aryl substitution, a class of substituents that had not been accessed with the α-chloroaldehyde inputs.^[8] Additionally, use of benzoic acid led to the formation of a novel nitro-dihydroisocoumarin. Preliminary mechanistic studies suggest that Rh is required for C–H bond addition to the nitroalkene and that Cu plays a critical role in isoquinolone formation.

Results and Discussion

After evaluating a number of reaction parameters for coupling amide 1a and nitroalkene 2a, optimal conditions were identified to be [Cp*Rh(MeCN)₃][SbF₆]₂ as catalyst, Cu(OAc)₂ as an additive, and hexafluoro-2-propanol (HFIP) as solvent at 80 °C (entry 1, Table 1). Under these conditions, isoquinolone 3a was formed in 75% NMR yield as a single regioisomer. The solvents 1,2-dichloroethane and 1,4-dioxane are commonly used in Rh(III)-catalyzed C-H functionalization reactions, but resulted in greatly reduced reaction yields (entries 2 and 3). We also explored 2,2,2-trifluoroethanol (TFE) as a less expensive alternative to HFIP, but a significantly lower yield was observed (entry 4). No product was obtained when [Cp*Rh(MeCN)₃][SbF₆]₂ was excluded (entry 5). Altering the catalyst system to [RuCI₂(p-cymene)]₂ as a precatalyst and AgSbF₆ as the chloride abstractor resulted in only a 12% yield of 3a (entry 6). No product was observed when using the related preformed Co catalyst [Cp*Co(MeCN)₃][SbF₆]₂ (entry 7). In the absence of Cu(OAc)₂, a very low yield of 3a was observed along with significant unidentified decomposition byproducts (entry 8), and when only 20 mol % of Cu(OAc)₂ was employed, only a 16% yield of 3a was observed (entry 9). Cu(OTf)₂, FeCl₃, and In(OTf)₃ have also been previously reported to catalyze annulation/denitration reactions for the synthesis of various aza-fused heterocycles, but in place of Cu(OAc)₂ did not provide product 3a (entries 10–12).^[10] Other first-row transition-metal acetates, particularly Zn(OAc)₂, have been reported to be effective in Rh(III)-catalyzed annulation reactions.^[11] However, Zn(OAc)₂and Fe(OAc)₂ resulted in lower yields of 26% and 54%, respectively (entries 13 and 14).

Table 1.

Control Reactions.^[a,b]

Entry[a]	Variation from standard conditions	NMR Yield 3a [%][b]
1	none	75
2	DCE as solvent	27
3	1,4-dioxane as solvent	33
4	TFE as solvent	36
5	no [Cp*Rh(MeCN)3][SbF6]2	0
6	[RuCl2(p-cymene)]2 and AgSbF6 instead of [Cp*Rh(MeCN)3][SbF6]2	12
7	[Cp*Co(MeCN)3][SbF6]2 instead of [Cp*Rh(MeCN)3][SbF6]2	0
8	no Cu(OAc)2	7[c]
9	20 mol % Cu(OAc)2	16
10	Cu(OTf)2 instead of Cu(OAc)2	0
11	FeCl3 instead of Cu(OAc)2	0
12	In(OTf)3 instead of Cu(OAc)2	0
13	Zn(OAc)2 instead of Cu(OAc)2	26
14	Fe(OAc)2 instead of Cu(OAc)2	54

^[a]Standard conditions: 0.15 mmol of 1a and 0.10 mmol of 2a with [Cp*Rh(MeCN)₃][SbF₆]₂ and Cu(OAc)₂ in HFIP (0.1 M) at 80 °C for 20 h.

^[b]Yields determined by ¹H NMR spectroscopic analysis relative to SiMe₃Ph as an external standard.

^[c]A 40% yield as determined by ¹H NMR was obtained for nitroalkene addition without cyclization (analogous to 5 in Table 4).

With optimized conditions in hand, we next explored the scope of the nitroalkene component (Table 2). Isoquinolone 3a was isolated by silica gel chromatography in 85% yield. Additional aliphatic nitroalkenes bearing benzyl, cyclohexyl, and isopropyl substituents afforded products 3b, 3c, and 3d, respectively, in good yields. A range of aromatic β-nitrostyrenes were also effective coupling partners in this reaction, including electron-neutral (3e), electron-rich (3f), electron-poor (3g), and ortho-substituted (3h) derivatives. These aryl-substituted products (3e-3h) are significant as they have not been prepared with any previously reported C–H functionalization methods, including the recently reported Rh(III)-catalyzed annulation with α-chloroaldehydes.^[8]

Table 2.

Nitroalkene scope.^[a,b]

^[a]Conditions: 0.45 mmol of 1a and 0.30 mmol of 2a with [Cp*Rh(MeCN)₃][SbF₆]₂ and Cu(OAc)₂ in HFIP (0.1 M) at 80 °C for 20 h.

^[b]Isolated yield after silica gel chromatography.

We next explored the scope of the C–H functionalization substrate (Table 3). In addition to the N-methoxyamides, the N-isopropoxy substituted benzamide gave product 3i in 82% yield. Electron-rich (3j, 3m, and 3n) and electron-poor (3l) C–H functionalization substrates all provided good to excellent yields of the isoquinolone products. When substituents were incorporated at the meta-position, exclusive regioselectivly for C–H functionalization at the least hindered site was observed (3j, 3k, and 3l). Additionally, alkenyl N-methoxyamides performed well, providing 2-pyridone products 3o and 3p in good yields. The thiophene-containing C–H functionalization substrate also afforded product 3q in good yield. The less acidic N-methyl- and N-phenylbenzamides resulted in only trace amounts of isoquinolone products 3r and 3s along with some recovered starting material and unidentified decomposition byproducts.

Table 3.

C–H functionalization substrate scope.^[a,b]

^[a]Conditions: 0.45 mmol of 1a and 0.30 mmol of 2a with [Cp*Rh(MeCN)₃][SbF₆]₂ and Cu(OAc)₂ in HFIP (0.1 M) at 80 °C for 20 h.

^[b]Isolated yield after silica gel chromatography.

The reaction is amenable to benchtop setup (Scheme 2). When performed on a 1 mmol scale, taking no precaution to exclude air or moisture, the pure product was obtained in 68% yield.

Scheme 2.

Benchtop reaction set up on 1 mmol scale.

In addition to N-methoxyamides, benzoic acid as a C–H functionalization substrate provided the interesting nitro-substituted dihydroisocoumarin 4 in good yield and as a single diastereomer under slightly modified conditions (Scheme 3). This unconventional product is most likely formed as a result of oxidative cyclization after nitroalkene addition (vide infra). Although this type of heterocycle has not previously been reported, α-acyloxynitroalkanes have been observed.^[12]

Scheme 3.

Formation of nitro-dihydroisocoumarin 4.

The relative stereochemistry of 4 could not be assigned by NMR spectroscopy owing to the absence of comparable structures of this kind and because only one of the two possible diastereomers was formed. Direct assignment of the relative stereochemistry by single crystal X-ray diffraction was not feasible because 4 is an oil at room temperature. This obstacle was circumvented by a single-step crystallization of an inclusion compound in which compound 4 was encapsulated within a member of a well-established family of hydrogen-bonded host frameworks formed from guanidinium cations and organosulfonates.^[13] Specifically, the guest-free apohost (guanidinium)₂(1,2-bis(4-sulfonatophenyl)ethane) (G₂BSPE) was dissolved in a methanol:water solution. Compound 4 then was added, and the solvent was allowed to evaporate slowly to afford prismatic crystals of the inclusion compound G₂BSPE⊃(4)₂. Single crystal X-ray diffraction revealed that G₂BSPE⊃(4)₂ refined well in the Pbca space group (R = 0.0530), with the framework adopting the “continuous zigzag brick” architecture that characteristically has orthorhombic symmetry. The BSPE components serve as pillars that support hydrogen-bonded quasihexagonal sheets of complementary guanidinium and sulfonate ions, creating pockets among the pillars in the crystallographic ab plane occupied by racemic pairs of compound 4 (Figure S2). The crystal structure provides an unambiguous assignment of the relative stereochemistry of compound 4, wherein the nitro and phenylethyl substituents adopt a trans configuration (Figure 1).

Figure 1.

The racemic pair of 4 encapsulated as guests in G₂BSP⊃(4)₂ illustrating the trans configuration.

To investigate the mechanism of this Rh(III)-catalyzed annulation reaction, we sought to understand the role of Cu(OAc)₂. Based on previously published work on the Rh(III)-catalyzed C–H bond addition to nitroalkenes, we presume that Rh(III)-catalyzed formation of the nitroalkane intermediate is not dependent on Cu(OAc)₂.^[9] We therefore hypothesized that Cu(OAc)₂ could mediate the intramolecular cyclization and denitration because previously reported syntheses of various aza-fused heterocycles have relied on Lewis acid catalyzed cyclizations of nitroalkenes.^[10] To test this hypothesis, we synthesized the proposed nitroalkane reaction intermediate 5 (see Experimental Section), which was subjected to a variety of reaction conditions (Table 4). When 5 was heated at 80 °C in HFIP without Rh and Cu, isoquinolone 3e was not detected, indicating that cyclization is not thermally or solvent mediated. In contrast, subjecting 5 to one equivalent of Cu(OAc)₂ resulted in a 60% NMR yield of 3e (entry 2). Additionally, subjecting 5 to 10 mol % of [Cp*Rh(MeCN)₃][SbF₆]₂ provided a 10% NMR yield of 3e (entry 3). This result indicates that while Rh(III) is capable of effecting cyclization, the reaction does not proceed in a catalytic fashion.

Table 4.

Mechanistic Experiments.

Entry[a]	Additives	Yield 3e [%][b]
1	none	0
2	Cu(OAc)2 (1 equiv)	60%
3	[Cp*Rh(MeCN)3][SbF6]2 (10 mol %)	10%

^[a]Conditions: 0.05 mmol of 5 in HFIP (0.1 M) at 80 °C for 20 h.

^[b]Yields determined by ¹H NMR spectroscopic analysis relative to SiMe₃Ph as an external standard.

Plausible mechanisms for the Rh(III)-catalyzed annulation of N-methoxyamides and nitroalkenes are shown in Scheme 4. Concerted/metalation deprotonation of N-methoxyamide 1 forms rhodacycle 6. Coordination and insertion of nitroalkene 2 provides rhodium nitronate 7. A related RhIII nitronate has been isolated and characterized by X-ray structural analysis.^[9a] From 7, two plausible pathways could provide isoquinolone 3. In pathway A, protonolysis regenerates the active rhodium catalyst with release of nitroalkane 8. Based on the findings shown in Table 4, nitroalkane 8 can undergo cyclization and denitration as mediated by Cu(OAc)₂. Another possible mechanism is shown in pathway B. Reductive elimination of 7 would give dihydroisoquinolone 9 and a reduced Rh(I) species that would be reoxidized back to the active Rh(III) catalyst by Cu(OAc)₂. Elimination of the nitro group from 9 would then provide isoquinolone 3.^[10]

Scheme 4.

Proposed mechanism.

Conclusions

We have developed a Rh(III)-catalyzed synthesis of isoquinolones and 2-pyridones by the annulation of N-methoxyamides and nitroalkenes. Aliphatic and aromatic nitroalkenes are effective in this reaction as are aromatic, alkenyl, and heteroaromatic C–H bonds. This transformation selectively provides the 4-substituted regioisomer, which is opposite to that reported for most other transition-metal catalyzed syntheses of isoquinolones. Employing benzoic acid in place of N-methoxyamide results in a unique nitro-dihydroisocoumarin. Determination of the structure and relative stereochemistry of this compound alone by single crystal X-ray diffraction was not feasible because it is an oil at room temperature. Inclusion of the nitro-dihydroisocoumarin in a hydrogen-bonded framework through a simple single-step crystallization, however, enabled determination of its molecular structure with unambiguous assignment of relative stereochemistry.

Experimental Section

General Procedure for the Synthesis of Isoquinolones and 2-Pyridones:

In a N₂-filled glove box, an oven-dried 2–5 mL Biotage® microwave vial with a stir bar was charged with the indicated nitroalkene (2) (0.30 mmol, 1.0 equiv), the indicated C–H functionalization substrate (1) (0.45 mmol, 1.5 equiv), [Cp*Rh(MeCN)₃][SbF₆]₂ (25 mg, 0.03 mmol, 0.10 equiv), Cu(OAc)₂ (54 mg, 0.30 mmol, 1.0 equiv), and HFIP (3.0 mL, [0.1 M]). The vial was then sealed and placed in a preheated oil bath at 80 °C, with vigorous stirring. After 20 h, the reaction vial was removed from the oil bath and allowed to cool to ambient temperature. The reaction mixture was concentrated and purified by silica gel chromatography to give the indicated product (3).

2-Methoxy-4-phenethylisoquinolin-1(2H)-one (3a):

The general procedure was followed using nitroalkene 2a (53 mg, 0.30 mmol, 1.0 equiv) and amide 1a (68 mg, 0.45 mmol, 1.5 equiv). Purification by silica gel chromatography (2:1 hexanes/ethyl acetate) provided the product 3a (71 mg, 85% yield) as a white solid (mp = 83 – 85 °C). IR (neat): 3090, 3028, 2944, 1651, 1622, 1600 cm⁻¹. ¹H NMR (600 MHz, Chloroform-d) δ 8.54 (d, J = 8.1 Hz, 1H), 7.77 – 7.68 (m, 2H), 7.59 – 7.49 (m, 1H), 7.29 (t, J = 7.3 Hz, 2H), 7.22 (t, J = 7.3 Hz, 1H), 7.14 (d, J = 7.5 Hz, 2H), 6.96 (s, 1H), 3.99 (s, 3H), 3.04 – 2.94 (m, 4H). ¹³C NMR (151 MHz, Chloroform-d) δ 157.7, 141.0, 135.7, 132.4, 128.62, 128.61, 128.5, 127.7, 127.4, 126.9, 126.4, 123.0, 115.4, 64.3, 35.6, 31.3. HRMS-ESI (m/z): [M+H]⁺ calcd for C₁₈H₁₈NO₂⁺, 280.1332; found, 280.1340.

4-Benzyl-2-methoxyisoquinolin-1(2H)-one (3b):

The general procedure was followed using nitroalkene 2b (49 mg, 0.30 mmol, 1.0 equiv) and amide 1a (68 mg, 0.45 mmol, 1.5 equiv). Purification by silica gel chromatography (2:1 hexanes/ethyl acetate) provided the product 3b (52 mg, 65% yield) as a white solid (mp = 91 – 92 °C, lit. mp = 95 – 96 °C). ¹H NMR (600 MHz, Chloroform-d) δ 8.52 (d, J = 8.0 Hz, 1H), 7.67 – 7.57 (m, 2H), 7.50 (t, J = 7.2 Hz, 1H), 7.32 (t, J = 7.2 Hz, 2H), 7.29 – 7.20 (m, 3H), 7.05 (s, 1H), 4.08 (s, 3H), 4.05 (s, 2H). ¹³C NMR (151 MHz, Chloroform-d) δ 157.9, 138.6, 135.9, 132.4, 128.9, 128.8, 128.6, 128.4, 127.7, 127.0, 126.8, 123.7, 115.3, 64.5, 35.6. Spectral characterization data matches previously reported data for the same compound.^[8]

4-Cyclohexyl-2-methoxyisoquinolin-1(2H)-one (3c):

A modification of the general procedure was followed using nitroalkene 2c (47 mg, 0.30 mmol, 1.0 equiv) and amide 1a (68 mg, 0.45 mmol, 1.5 equiv). After heating at 80 °C for 20 h, the crude reaction mixture was concentrated, dissolved in EtOAc (20 mL) and 0.1 M Na₂CO³ (20 mL), and transferred to a separatory funnel. The layers were separated and the aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine, dried over Na₂SO⁴, and concentrated under reduced pressure. Purification by silica gel chromatography (2:1 hexanes/ethyl acetate) provided the product 3c (49 mg, 64% yield) as a white solid (mp = 73 – 74 °C). IR (neat): 3028, 2952, 1654, 1624, 1601 cm⁻¹. ¹H NMR (600 MHz, Chloroform-d) δ 8.51 (d, J = 8.1 Hz, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.67 (m, 1H), 7.48 (m, 1H), 7.12 (s, 1H), 4.09 (s, 3H), 2.91 – 2.78 (m, 1H), 2.01 (d, J = 13.2 Hz, 2H), 1.93 – 1.85 (m, 2H), 1.81 (d, J = 13.2 Hz, 1H), 1.55 – 1.43 (m, 2H), 1.41 – 1.21 (m, 3H). ¹³C NMR (151 MHz, Chloroform-d) δ 157.5, 135.6, 132.1, 128.4, 127.7, 126.7, 125.2, 122.7, 122.2, 64.3, 36.9, 33.6, 27.0, 26.4. HRMS-ESI (m/z): [M+H]⁺ calcd for C₁₆H₂₀NO₂⁺, 258.1489; found, 258.1485.

4-Isobutyl-2-methoxyisoquinolin-1(2H)-one (3d):

The general procedure was followed using nitroalkene 2d (39 mg, 0.30 mmol, 1.0 equiv) and amide 1a (68 mg, 0.45 mmol, 1.5 equiv). Purification by silica gel chromatography (2:1 hexanes/ethyl acetate) provided the product 3d (52 mg, 75% yield) as a white solid (mp = 63 – 64 °C). IR (neat): 3017, 2956, 2935, 1655, 1622, 1599 cm⁻¹. ¹H NMR (600 MHz, Chloroform-d) δ 8.51 (d, J = 8.1 Hz, 1H), 7.67 (t, J = 7.5 Hz, 1H), 7.63 (d, J = 8.1 Hz, 1H), 7.50 (t, J = 7.5 Hz, 1H), 7.12 (s, 1H), 4.08 (s, 3H), 2.52 (d, J = 7.1 Hz, 2H), 1.98 – 1.90 (m, 1H), 0.96 (d, J = 6.6 Hz, 6H). ¹³C NMR (151 MHz, Chloroform-d) δ 157.8, 136.1, 132.1, 128.4, 127.7, 127.5, 126.8, 123.5, 115.7, 64.4, 38.9, 28.0, 22.7. HRMS-ESI (m/z): [M+H]⁺ calcd for C₁₄H₁₈NO₂⁺, 232.1332; found, 232.1339.

2-Methoxy-4-phenylisoquinolin-1(2H)-one (3e):

The general procedure was followed using nitroalkene 2e (45 mg, 0.30 mmol, 1.0 equiv) and amide 1a (68 mg, 0.45 mmol, 1.5 equiv). Purification by silica gel chromatography (2:1 hexanes/ethyl acetate) provided the product 3e (55 mg, 73% yield) as a thick clear oil. IR (neat): 3064, 2936, 1656, 1619, 1598 cm⁻¹. ¹H NMR (600 MHz, Chloroform-d) δ 8.57 (d, J = 8.0 Hz, 1H), 7.62 (t, J = 7.5 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.53 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.2 Hz, 2H), 7.46 – 7.40 (m, 3H), 7.32 (s, 1H), 4.15 (s, 3H). ¹³C NMR (151 MHz, Chloroform-d) δ 157.7, 135.7, 135.6, 132.3, 130.1, 128.9, 128.24, 128.19, 128.1, 127.4, 127.2, 125.1, 119.6, 64.6. HRMS-ESI (m/z): [M+H]⁺ calcd for C₁₆H₁₄NO₂⁺, 252.1019; found, 252.1018.^[14]

2-Methoxy-4-(4-methoxyphenyl)isoquinolin-1(2H)-one (3f):

The general procedure was followed using nitroalkene 2f (54 mg, 0.30 mmol, 1.0 equiv) and amide 1a (68 mg, 0.45 mmol, 1.5 equiv). Purification by silica gel chromatography (2:1 hexanes/ethyl acetate) provided the product 3f (52 mg, 62% yield) as a white solid (mp = 121 – 122 °C). IR (neat): 3076, 2936, 1656, 1618, 1606 cm⁻¹. ¹H NMR (600 MHz, Chloroform-d) δ 8.55 (d, J = 7.9 Hz, 1H), 7.61 (t, J = 7.5 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.52 (t, J = 7.5 Hz, 1H), 7.33 (d, J = 8.2 Hz, 2H), 7.28 (s, 1H), 7.01 (d, J = 8.2 Hz, 2H), 4.14 (s, 3H), 3.88 (s, 3H). ¹³C NMR (151 MHz, Chloroform-d) δ 159.5, 157.7, 136.1, 132.3, 131.2, 128.2, 128.0, 127.7, 127.4, 127.1, 125.2, 119.2, 114.3, 64.6, 55.5. HRMS-ESI (m/z): [M+H]⁺ calcd for C₁₇H₁₆NO₃⁺, 282.1125; found, 282.1129.

2-Methoxy-4-(4-(trifluoromethyl)phenyl)isoquinolin-1(2H)-one (3g):

The general procedure was followed using nitroalkene 2g (65 mg, 0.30 mmol, 1.0 equiv) and amide 1a (68 mg, 0.45 mmol, 1.5 equiv). Purification by silica gel chromatography (2:1 hexanes/ethyl acetate) provided the product 3g (47 mg, 49% yield) as a white solid (mp = 104 – 105 °C). IR (neat): 3074, 2933, 1660, 1612, 1603 cm⁻¹. ¹H NMR (600 MHz, Chloroform-d) δ 8.57 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 8.1 Hz, 2H), 7.67 – 7.63 (m, 1H), 7.59 – 7.54 (m, 3H), 7.51 (d, J = 8.1 Hz, 1H), 7.34 (s, 1H), 4.16 (s, 3H). ¹³C NMR (151 MHz, Chloroform-d) δ 157.7, 139.4, 135.1, 132.6, 130.5, 130.4 (q, J = 32.8 Hz), 128.7, 128.5, 127.53, 127.49, 125.9 (q, J = 3.6 Hz), 124.7, 124.2 (q, J = 272.1 Hz), 118.1, 64.8. ¹⁹F NMR (470 MHz, Chloroform-d) δ −62.60. HRMS-ESI (m/z): [M+H]⁺ calcd for C₁₇H₁₃F₃NO₂⁺, 320.0893; found, 320.0893.

4-(2-Chlorophenyl)-2-methoxyisoquinolin-1(2H)-one (3h):

The general procedure was followed using nitroalkene 2h (55 mg, 0.30 mmol, equiv) and amide 1a (68 mg, 0.45 mmol, 1.5 equiv). Purification by silica gel chromatography (2:1 hexanes/ethyl acetate) provided the product 3h (42 mg, 49% yield) as a white solid (mp = 112 – 113 °C). IR (neat): 3059, 2997, 2946, 1663, 1625, 1606 cm⁻¹. ¹H NMR (600 MHz, Chloroform-d) δ 8.55 (d, J = 8.0 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 7.56 – 7.50 (m, 2H), 7.43 – 7.35 (m, 3H), 7.31 (s, 1H), 7.16 (d, J = 8.1 Hz, 1H), 4.16 (s, 3H). ¹³C NMR (151 MHz, Chloroform-d) δ 157.9, 135.6, 135.2, 134.1, 132.8, 132.4, 130.05, 129.99, 129.2, 128.1, 127.20, 127.17, 125.2, 116.6, 64.7. HRMS-ESI (m/z): [M+H]⁺ calcd for C₁₆H₁₃ClNCO₂⁺, 286.0629; found, 286.0630.

2-lsopropoxy-4-phenethylisoquinolin-1(2H)-one (3i):

The general procedure was followed using nitroalkene 2a (53 mg, 0.30 mmol, 1.0 equiv) and amide 1b (81 mg, 0.45 mmol, 1.5 equiv). Purification by silica gel chromatography (3:1 hexanes/ethyl acetate) provided the product 3i (76 mg, 82% yield) as a yellow oil. IR (neat): 3021, 2981, 1657, 1623, 1603 cm⁻¹. ¹H NMR (600 MHz, Chloroform-d) δ 8.52 (d, J = 8.5 Hz, 1H), 7.75 – 7.70 (m, 2H), 7.55 – 7.50 (m, 1H), 7.28 (t, J = 7.5 Hz, 2H), 7.20 (t, J = 7.4 Hz, 1H), 7.14 (d, J = 7.1 Hz, 2H), 6.91 (s, 1H), 4.75 – 4.66 (m, 1H), 3.03 – 2.96 (m, 4H), 1.24 (d, J = 6.2 Hz, 6H). ¹³C NMR (151 MHz, Chloroform-d) δ 158.5, 141.0, 135.7, 132.2, 129.8, 128.61, 128.59, 128.5, 127.6, 126.8, 126.3, 122.9, 114.1, 78.5, 35.5, 31.2, 20.7. HRMS-ESI (m/z): [M+H]⁺ calcd for C₂₀H₂₂NO₂⁺, 308.1645; found, 308.1648.

2-Methoxy-7-methyl-4-phenethylisoquinolin-1(2H)-one (3j):

The general procedure was followed using nitroalkene 2a (53 mg, 0.30 mmol, 1.0 equiv) and amide 1c (74 mg, 0.45 mmol, 1.5 equiv). Purification by silica gel chromatography (2:1 hexanes/ethyl acetate) provided the product 3j (64 mg, 73% yield) as a wax. IR (neat): 3028, 2933, 1657, 1612, 1502 cm⁻¹. ¹H NMR (600 MHz, Chloroform-d) δ 8.33 (s, 1H), 7.62 (d, J = 8.3 Hz, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7.28 (t, J = 7.5 Hz, 2H), 7.21 (t, J = 7.3 Hz, 1H), 7.12 (d, J = 7.5 Hz, 2H), 6.90 (s, 1H), 3.97 (s, 3H),3.01– 2.91 (m, 4H), 2.50 (s, 3H). ¹³C NMR (151 MHz, Chloroform-d) δ 157.6, 141.0, 137.1, 133.8, 133.4, 128.6, 128.5, 128.1, 127.5, 126.4, 126.3, 122.9, 115.3, 64.2, 35.6, 31.3, 21.4. HRMS-ESI (m/z): [M+H]⁺ calcd for C₁₉H₂₀NO₂⁺, 294.1489; found, 294.1487.

7-Bromo-2-methoxy-4-phenethylisoquinolin-1(2H)-one (3k):

The general procedure was followed using nitroalkene 2a (53 mg, 0.30 mmol, 1.0 equiv) and amide 1d (104 mg, 0.45 mmol, 1.5 equiv). Purification by silica gel chromatography (2:1 hexanes/ethyl acetate) provided the product 3k (84 mg, 78% yield) as a white solid (mp = 86 – 88 °C). IR (neat): 3067, 3021, 2937, 1653, 1619, 1594 cm⁻¹. ¹H NMR (600 MHz, Chloroform-d) δ 8.66 (d, J = 2.2 Hz, 1H), 7.80–7.78 (m, 1H), 7.58 (d, J = 8.7 Hz, 1H), 7.29 (t, J = 7.5 Hz, 2H), 7.22 (t, J = 7.4 Hz, 1H), 7.11 (d, J =7.1 Hz, 2H), 6.95 (s, 1H), 3.97 (s, 3H), 2.99 – 2.92 (m, 4H). ¹³C NMR (151 MHz, Chloroform-d) δ 156.6, 140.7, 135.5, 134.5, 131.1, 129.1, 128.7, 128.6, 127.9, 126.5, 124.8, 121.1, 114.9, 64.4, 35.5, 31.2. HRMS-ESI (m/z): [M+H]⁺ calcd for C₁₈H₁₇BrNO₂⁺, 358.0437; found, 358.0435.

2-Methoxy-4-phenethyl-7-(trifluoromethyl)isoquinolin-1(2H)-one (3l):

The general procedure was followed using nitroalkene 2a (53 mg, 0.30 mmol, 1.0 equiv) and amide 1e (99 mg, 0.45 mmol, 1.5 equiv). Purification by silica gel chromatography (2:1 hexanes/ethyl acetate) provided the product 3I (82 mg, 79% yield) as a clear oil. IR (neat): 3066, 3024, 2940, 1664, 1622 cm⁻¹. ¹H NMR (600 MHz, Chloroform-d) δ 8.81 (s, 1H), 7.90 (d, J = 8.5 Hz, 1H), 7.83 (d, J = 8.5 Hz, 1H), 7.29 (t, J = 7.6 Hz, 2H), 7.22 (t, J = 7.3 Hz, 1H), 7.11 (d, J = 7.4 Hz, 2H), 7.03 (s, 1H), 3.99 (s, 3H), 3.04 – 2.94 (m, 4H). ¹³C NMR (151 MHz, Chloroform-d) δ 157.1, 140.5, 138.2, 129.7, 128.9 (q, J = 33.2 Hz), 128.7, 128.6, 128.5 (q, J = 3.3 Hz), 127.6, 126.5, 126.2 (q, J = 4.1 Hz), 124.0, 123.9 (q, J = 272.3 Hz), 114.7, 64.5, 35.5, 31.2. ¹⁹F NMR (470 MHz, Chloroform-d) δ −62.42. HRMS-ESI (m/z): [M+H]⁺ calcd for C₁₉H₁₇F₃NO₂⁺, 348.1206; found, 348.1207.

2,6-Dimethoxy-4-phenethylisoquinolin-1(2H)-one (3m):

The general procedure was followed using nitroalkene 2a (53 mg, 0.30 mmol, 1.0 equiv) and amide 1f (82 mg, 0.45 mmol, 1.5 equiv). Purification by silica gel chromatography (2:1 hexanes/ethyl acetate) provided the product 3m (63 mg, 68% yield) as a tan solid (mp = 66 – 67 °C). IR (neat): 3077, 3000, 2943, 1655, 1625, 1598 cm⁻¹. ¹H NMR (600 MHz, Chloroform-d) δ 8.44 (d, J = 8.9 Hz, 1H), 7.29 (t, J = 7.3 Hz, 2H), 7.22 (t, J = 7.2 Hz, 1H), 7.14 (d, J = 7.3 Hz, 2H), 7.10 (d, J = 8.9 Hz, 1H), 7.03 (s, 1H), 6.95 (s, 1H), 3.98 (s, 3H), 3.92 (s, 3H), 3.02 – 2.90 (m, 4H). ¹³C NMR (151 MHz, Chloroform-d) δ 162.9, 157.5, 141.0, 137.8, 130.5, 128.6, 127.9, 126.4, 121.3, 115.5, 114.7, 105.1, 64.4, 55.6, 35.3, 31.4. HRMS-ESI (m/z): [M+H]⁺calcd for C₁₉H₂₀NO₃⁺, 310.1438; found, 310.1432.

2,6,7-Trimethoxy-4-phenethylisoquinolin-1(2H)-one (3n):

The general procedure was followed using nitroalkene 2a (53 mg, 0.30 mmol, 1.0 equiv) and amide 1g (95 mg, 0.45 mmol, 1.5 equiv). Purification by silica gel chromatography (1:2 hexanes/ethyl acetate) provided the product 3n (89 mg, 87% yield) as a tan solid (mp = 105 – 107 °C). IR (neat): 3026, 2945, 2829, 1656, 1606 cm⁻¹. ¹H NMR (600 MHz, Chloroform-d) δ 7.87 (s, 1H), 7.28 (t, J = 7.4 Hz, 2H), 7.21 (t, J = 7.3 Hz, 1H), 7.13 (d, J = 7.8 Hz, 2H), 6.95 (s, 1H), 6.92 (s, 1H), 4.01 (s, 3H), 3.98 (s, 3H), 3.98 (s, 3H), 2.99 – 2.92 (m, 4H). ¹³C NMR (151 MHz, Chloroform-d) δ 157.1, 153.3, 149.1, 141.0, 131.1, 128.62, 128.58, 126.4, 125.8, 121.5, 114.9, 108.2, 103.3, 64.4, 56.3, 56.1, 35.4, 31.5. HRMS-ESI (m/z): [M+H]⁺ calcd for C₂₀H₂₂NO₄⁺, 340.1543; found, 340.1548.

1-Methoxy-3-methyl-5-phenethylpyridin-2(1H)-one (3o):

The general procedure was followed using nitroalkene 2a (53 mg, 0.30 mmol, 1.0 equiv) and amide 1h (52 mg, 0.45 mmol, 1.5 equiv). Purification by silica gel chromatography (1:1 hexanes/ethyl acetate) provided the product 3o (48 mg, 66% yield) as a white solid (mp = 71 – 72 °C). IR (neat): 3023, 2947, 2920, 2856, 1655, 1611 cm⁻¹. ¹H NMR (600 MHz, Chloroform-d) δ 7.28 (t, J = 7.5 Hz, 2H), 7.20 (t, J = 7.4 Hz, 1H), 7.10 (d, J = 7.5 Hz, 2H), 7.05(s, 1H), 7.00 (s, 1H), 3.97 (s, 3H), 2.82 (t, J = 7.7 Hz, 2H), 2.64 (t, J = 7.7 Hz, 2H), 2.17 (s, 3H). ¹³C NMR (151 MHz, Chloroform-d) δ 158.2, 140.5, 137.9, 132.0, 130.1, 128.7, 128.6, 126.4, 118.0, 64.5, 36.9, 33.6, 17.3.HRMS-ESI (m/z): [M+H]⁺ calcd for C₁₅H₁₈NO₂⁺, 244.1332; found, 244.1331.

1-Methoxy-5-phenethyl-3-phenylpyridin-2(1H)-one (3p):

The general procedure was followed using nitroalkene 2a (53 mg, 0.30 mmol, 1.0 equiv) and amide 1i (80 mg, 0.45 mmol, 1.5 equiv). Purification by silica gel chromatography (1:1 hexanes/ethyl acetate) provided the product 3p (55 mg, 60% yield) as a yellow oil. IR (neat): 3028, 2939, 1651, 1600, 1541 cm⁻¹. ¹H NMR (600 MHz, Chloroform-d) δ 7.66 (d, J = 7.1 Hz, 2H), 7.40 (t, J = 7.6 Hz, 2H), 7.36 – 7.29 (m, 4H), 7.23 (t, J = 7.4 Hz, 1H), 7.17 (d, J = 2.5 Hz, 1H), 7.14 (s, 1H), 7.13 (s, 1H)), 4.03 (s, 3H), 2.88 (t, J = 7.6 Hz, 2H), 2.74 (t, J = 7.6 Hz, 2H). ¹³C NMR (151 MHz, Chloroform-d) δ 157.0, 140.5, 138.6, 136.2, 133.4, 131.9, 128.74, 128.68, 128.3, 128.1, 126.5, 118.2, 64.6, 37.1, 33.7. HRMS-ESI (m/z): [M+H]⁺ calcd for C₂₀H₂₀NO₂⁺, 306.1489; found, 306.1490.

6-Methoxy-4-phenethylthieno[2,3-c]pyridin-7(6H)-one (3q):

The general procedure was followed using nitroalkene 2a (53 mg, 0.30 mmol,1.0 equiv) and amide 1j (71 mg, 0.45 mmol, 1.5 equiv). Purification by silica gel chromatography (1:1 hexanes/ethyl acetate) provided the product 3q (52 mg, 61% yield) as a yellow oil. IR (neat): 3086, 2930, 2857, 1648, 1596 cm⁻¹. ¹H NMR (600 MHz, Chloroform-d) δ 7.74 (d, J =5.2 Hz, 1H), 7.31 – 7.26 (m, 3H), 7.21 (t, J = 7.4 Hz, 1H), 7.11 (d, J = 7.2 Hz, 2H), 7.01 (s, 1H), 4.01 (s, 3H), 2.98 – 2.92 (m, 4H). ¹³C NMR (151 MHz, Chloroform-d) δ 154.2, 144.8, 140.7, 133.9, 131.3, 128.61, 128.61, 128.3, 126.4, 122.4, 114.8, 64.9, 36.0, 32.2. HRMS-ESI (m/z): [M+H]⁺ calcd for C₁₆H₁₆NO₂S⁺, 286.0896; found, 286.0892.

Scale up benchtop synthesis of 3a:

Taking no precaution to exclude air or moisture, a 10–20 mL Biotage® microwave vial with a stir bar was charged with the nitroalkene 2a (177 mg, 1.00 mmol, 1.00 equiv), amide 1a (227 mg, 1.50 mmol, 1.50 equiv), [Cp*Rh(MeCN)₃][SbF₆]₂ (83 mg, 0.10 mmol, 0.10 equiv), Cu(OAc)₂ (182 mg, 1.00 mmol, 1.00 equiv), and HFIP (10 mL, [0.1 M]) on the benchtop. The vial was then sealed and placed in a preheated oil bath at 80 °C, with vigorous stirring. After 20 h, the reaction vial was removed from the oil bath and allowed to cool to ambient temperature. The reaction mixture was concentrated and purified by silica gel chromatography (2:1 hexanes/ethyl acetate) to give the product 3a (191 mg, 68% yield) as a white solid. ¹H NMR (600 MHz, Chloroform-d) δ 8.54 (d, J = 8.0 Hz, 1H), 7.75 – 7.71 (m, 2H), 7.56 – 7.52 (m, 1H), 7.30 (t, J = 7.5 Hz, 2H), 7.22 (t, J = 7.4 Hz, 1H), 7.14 (d, J = 7.0 Hz, 2H), 6.97 (s, 1H), 3.99 (s, 3H), 3.03 – 2.95 (m, 4H). ¹³C NMR (151 MHz, Chloroform-d) δ 157.8, 141.1, 135.8, 132.4, 128.7, 128.65, 128.58, 127.6, 127.4, 127.0, 126.4, 123.0, 115.4, 64.4, 35.7, 31.4. Spectral characterization data is identical with the smaller scale reaction.

Synthesis of 3-nitro-4-phenethylisochroman-1-one (4):

In a N₂-filled glove box, an oven-dried 2–5 mL Biotage® microwave vial with a stir bar was charged with nitroalkene 2a (53 mg, 0.30 mmol, 1.0 equiv), benzoic acid (55 mg, 0.45 mmol, 1.5 equiv), [Cp*Rh(MeCN)₃][SbF₆]₂ (25 mg, 0.03 mmol, 0.10 equiv), Cu(OAc)₂ (109 mg, 0.60 mmol, 2.0 equiv), and HFIP (3.0 mL, [0.1 M]). The vial was then sealed and placed in a preheated oil bath at 100 °C, with vigorous stirring. After 20 h, the reaction vial was removed from the oil bath and allowed to cool to ambient temperature. The reaction mixture was concentrated and purified by silica gel chromatography (5:1 hexanes/ethyl acetate) to give the product 4 (54 mg, 61% yield) as a clear oil. IR (neat): 3016, 2975, 1759, 1564, 1370 cm⁻¹. ¹H NMR (600 MHz, Chloroform-d) δ 8.15 (d, J = 7.8 Hz, 1H), 7.60 (t, J = 7.5 Hz, 1 H), 7.48 (t, J = 7.7 Hz, 1H), 7.33 (t, J = 7.5 Hz, 2H), 7.27 – 7.23 (m, 1H), 7.20 (d, J = 7.6 Hz, 2H), 7.16 (d, J = 7.6 Hz, 1H), 6.14 (s, 1H), 3.66 (t, J = 7.4 Hz, 1H), 2.89 – 2.74 (m, 2H), 2.31 – 2.21 (m, 1H), 2.09 – 1.97 (m, 1H). ¹³C NMR (151 MHz, Chloroform-d) δ 160.2, 139.6, 137.5, 135.0, 130.9, 129.2, 129.0, 128.4, 128.1, 126.9, 122.6, 104.1, 41.3, 36.9, 32.9. HRMS-ESI (m/z): [M-NO₂]⁺ calcd for C₁₇H₁₅O₂⁺, 251.1067; found, 251.1068. Anal. Calcd for C₁₇H₁₅NO₄: C, 68.68; H, 5.09; N, 4.71. Found: C, 68.92; H, 5.17; N, 4.48.

Synthesis of N-methoxy-2-(2-nitro-1-phenylethyl)benzamide (5):

In a N₂-filled glove box, an oven-dried 2–5 mL Biotage® microwave vial with a stir bar was charged with nitroalkene 2e (45 mg, 0.30 mmol, 1.0 equiv), C–H functionalization substrate 1a (68 mg, 0.45 mmol, 1.5 equiv), [Cp*Rh(MeCN)₃][SbF₆]₂ (25 mg, 0.03 mmol, 0.10 equiv), and HFIP (3.0 mL, [0.1 M]). The vial was then sealed and placed in a preheated oil bath at 40 °C, with vigorous stirring. After 20 h, the reaction vial was removed from the oil bath and allowed to cool to ambient temperature. The reaction mixture was concentrated and purified by preparative thin layer chromatography (1:1 hexanes/ethyl acetate) to give 5 (20 mg, 22% yield) as a clear oil. IR (neat): 3171, 2972, 2817, 1652, 1552 cm⁻¹. ¹H NMR (600 MHz, Chloroform-d) δ 8.43 (s, 1H), 7.43 (t, J = 7.5 Hz, 1H), 7.37 – 7.22 (m, 8H), 5.47 (t, J = 8.1 Hz, 1H), 5.14 (dd, J = 13.3, 8.9 Hz, 1H), 5.00 (dd, J = 13.3, 7.4 Hz, 1H), 3.82 (s, 3H). ¹³C NMR (151 MHz, Chloroform-d) δ 167.3, 138.8, 138.7, 133.3, 131.4, 129.1, 128.2, 128.1, 127.9, 127.7, 127.6, 79.0, 64.7, 44.4. HRMS-ESI (m/z): [M+H]⁺ calcd for C₁₆H₁₇N₂O₄⁺, 301.1183; found, 301.1182.

Synthesis of crystalline (G₂BSPE)⊃(4)₂:

(Guanidinium)₂(1,2-bis(4-sulfonatophenyl)ethane) apohost (G₂BSPE) was prepared according to a previously reported method.¹⁵ Chlorosulfonic acid (4.43 mL, 7.88 g, 67.6 mmol) was added slowly via syringe to a chilled (−15 °C) round-bottom flask containing anhydrous chloroform (20 mL) and 1,2-biphenylethane (4.66 mL, 5.00 g, 29.4 mmol), all under a nitrogen atmosphere. After 15 min, the chloroform and excess chlorosulfonic acid were decanted from the oily residue. The oil was further rinsed with chloroform (20 mL), dissolved in acetone, and then treated with an acetone solution of G(BF₄). The G₂BSPE-(acetone)_n precipitate was filtered and dried under vacuum to give 9.22 g (20.5 mmol) of pure, white G₂BSPE apohost (70% yield). ¹H NMR (dimethyl sulfoxide-d₆, 400 MHz): δ 7.50 (d, 4H), 7.18 (d, 4H), 6.92 (s, 12H), 2.86 (s, 4H). Compound 4 (0.5 mg, 1.7 μmol) was added to a 13 × 100 mm borosilicate glass test tube containing the G₂BSPE apohost (0.5 mg, 1.1 μmol) dissolved in 0.5 mL of methanol and 0.2 mL of water. The test tube was sealed with Parafilm M, which was then pierced to create pinholes that allowed slow evaporation of the solvent. After three days, plate-shaped crystals of the inclusion compound G₂BSPE⊃(4)₂ formed on the wall of the test tube. Needle-shaped crystals of guest-free G₂BSPE formed concomitant with the G₂BSPE⊃(4)₂. Single-crystal X-ray diffraction revealed that (G₂BSPE)⊃(4)₂ crystallized in the Pbca space group (a = 15.005 Å, b = 12.771 Å, c = 26.519 Å).

Single crystal X-ray structure analysis:

A crystal of 4 was selected and mounted on a Bruker D8 APEX-II CCD diffractometer for data collection. The X-ray generated from a sealed Mo tube was monochromated with a graphite crystal and collimated with a 0.5 mm MONOCAP, providing a focused spot beam (Mo-Kα λ= 0.71073 Å). The temperature was controlled by an Oxford Cryosystems 700+ Cooler. The data were collected with the ω scan method at 100 K. The dataset was processed with the INTEGRATE program of the APEX2 software for reduction and cell refinement.¹⁶ Multi-scan absorption corrections were applied by the SCALE program for the area detector. The structure was solved by intrinsic phasing methods (SHELXT)¹⁷ and the structure models were completed and refined using the full-matrix least-square methods on F² (SHELXL).¹⁸ Non-hydrogen atoms in the structure were refined with anisotropic displacement parameters, and hydrogen atoms on carbons were placed in idealized positions (C-H = 0.95-1.00 Å) and included as riding with Uiso(H) = 1.2 or 1.5 Ueq(non-H). Selected crystallographic parameters for G₂BSPE⊃(4)₂ are listed in Table S1. Crystallographic data for G₂BSPE⊃(4)₂, including cif, fcf and hkl files, have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. 1841628. Copies of available material can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax: +44-(0)1223-336033 or deposit@ccdc.cam.ac.uk).