Stereoselective Synthesis of Benzosultam-Fused Tetrahydroquinazolines via [4+2]-Cycloaddition of Cyclic N-Sulfonyl Ketimines with 2-Aminophenyl Enones

Ji Won Han; Sung-Gon Kim

doi:10.1055/a-2567-4696

Synthesis, Table of Contents

Synthesis 2025; 57(13): 2075-2082
DOI: 10.1055/a-2567-4696

paper

Stereoselective Synthesis of Benzosultam-Fused Tetrahydroquinazolines via [4+2]-Cycloaddition of Cyclic N-Sulfonyl Ketimines with 2-Aminophenyl Enones

Ji Won Han

,

Sung-Gon Kim∗

Abstract

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Key words

[4+2]-cycloaddition - benzosultams - 2-aminophenyl enones - cyclic N-sulfonyl ketimines - tetrahydroquinazolines

Benzosultam, an N-heterocycle characterized by a sulfonamide functionality within its ring structure, is widely encountered in biologically significant natural products and pharmaceuticals (Figure [1]).[1] Renowned as privileged motifs in drug discovery, they offer a diverse range of biological activities, immunostimulant, antimicrobial, aldose reductase inhibition, and anti-inflammatory, to name a few. Beyond their pharmacological appeal, benzosultams are highly adaptable intermediates in organic chemistry, serving as chiral auxiliaries and ligands in asymmetric synthesis, as well as functioning as protecting groups and directed metalation groups, thereby broadening their utility in the development of complex molecules for both pharmaceutical research and synthetic methodologies.[2] With their notable biological profiles and pivotal significance in synthetic chemistry, benzosultams have increasingly captivated the interest of synthetic organic chemists. This focus has stimulated a variety of innovative synthetic strategies, culminating in a broad spectrum of benzosultam derivatives.[3]

Recently, we have developed stereoselective methods for synthesizing N,N-heterocyclic tetrahydroquinazolines via cycloaddition reactions starting from 2-aminophenyl enones (Scheme [1]).[4] Specifically, the [4+2]-cycloaddition of isatin-derived ketimines with 2-aminophenyl enones, catalyzed by bifunctional squaramide, yielded enantioenriched spirooxindole-tetrahydroquinazolines with excellent enantio- and diastereoselectivities (up to 95% ee and >20:1 dr) (Scheme [1a]). Additionally, the [4+2]-cycloaddition of cyclic N-sulfimines with 2-aminophenyl enones, under similar catalytic conditions, afforded enantioenriched fused tetrahydroquinazolines, also with high enantio- and diastereoselectivities (up to 94% ee and >20:1 dr) (Scheme [1b]). Building on our previous work, herein we report our findings on the base-catalyzed [4+2]-cycloaddition reaction of cyclic N-sulfonyl ketimines[5] [6] with 2-aminophenyl enones,[7] resulting in the successful synthesis of highly functionalized benzosultam-fused tetrahydroquinazolines featuring a quaternary carbon center (Scheme [1c]).

Figure 1 Representative bioactive benzosultam structures

Scheme 1 [4+2]-Cycloaddition of 2-aminophenyl enones to synthesize tetrahydroquinazolines

Table 1 Optimization of the [4+2]-Cycloaddition of 2-Aminophenyl Enone with Cyclic N-Sulfonyl Ketimine^a

Entry	Base	Solvent	Time (h)	Yield (%)^b	dr^c
1	Na₂CO₃	CH₂Cl₂	24	63	5:1
2	K₂CO₃	CH₂Cl₂	3	79	15:1
3	Cs₂CO₃	CH₂Cl₂	2	69	16:1
4	DMAP	CH₂Cl₂	3	48	2:1
5	DBU	CH₂Cl₂	3	8	>20:1
6	Et₃N	CH₂Cl₂	48	n.r.	–
7	K₂CO₃	CHCl₃	3	59	7:1
8	K₂CO₃	MeCN	2	58	7:1
9	K₂CO₃	EtOAc	2	84	20:1
10	K₂CO₃	toluene	3	65	7:1
11	K₂CO₃	MeOH	2	63	7:1

^a Reaction conditions: 1a (0.10 mmol), 2a (0.15 mmol), solvent (1.0 mL), base, r.t.

^b Isolated yield after chromatographic purification; n.r. = no reaction.

^c Determined by ¹H NMR analysis of the crude product.

Initially, we explored the feasibility of using a base catalyst in the [4+2]-cycloaddition process to construct benzosultam-fused tetrahydroquinazolines. Ethyl benzo[d]isothiazole-3-carboxylate 1,1-dioxide (1a) and (E)-3-(2-aminophenyl)-1-phenylprop-2-en-1-one (2a) were selected as model substrates (Table [1]). The reaction conducted in CH₂Cl₂ at room temperature with Na₂CO₃ (20 mol%) as a base catalyst yielded the desired product 3aa in 63% yield and a diastereomeric ratio of 5:1 (entry 1). Encouraged by this result, we subsequently conducted the reaction using different bases, to optimize the reaction conditions. Among the inorganic carbonate bases tested, chemical reactivity and stereocontrol improved with the increasing size of the countercation (entries 1–3). In contrast, reactions with organic bases resulted in low yields or no reaction at all (entries 4–6). K₂CO₃ emerged as the most effective base, affording the best balance of yield and stereoselectivity (entry 2). To further refine the reaction conditions, we screened various organic solvents, including CH₂Cl₂, CHCl₃, MeCN, EtOAc, toluene, and MeOH, using K₂CO₃ as the base (entries 2 and 7–11). Among these, EtOAc proved to be the optimal solvent. The reaction conducted in EtOAc with K₂CO₃ (20 mol%) led to a significant improvement, achieving an 84% yield with excellent stereoselectivity (20:1 dr) (entry 9).

Scheme 2 Substrate scope of 2-aminophenyl enones. Reagents and conditions: 1a (0.20 mmol), 2 (0.30 mmol), K₂CO₃ (0.040 mmol), EtOAc (2.0 mL), r.t. Isolated yield after chromatographic purification is reported. Diastereomeric ratio was determined by ¹H NMR analysis of the crude product.

With the optimized reaction conditions established, we investigated the scope and generality of 2-aminophenyl enones 2 in the [4+2]-cycloaddition reaction (Scheme [2]). The results revealed that this methodology accommodates a wide range of 2-aminophenyl enones with varying electronic substituents, affording the desired benzosultam-fused tetrahydroquinazoline products (3aa–am) in high yields and diastereoselectivities. Substrates bearing electron-donating or electron-withdrawing substituents on the aromatic ring of the enone provided the corresponding tetrahydroquinazoline products (3ab–ah) in consistently high yields (78–86%). Interestingly, substrates with C4-substituents on the aromatic ring of the enone exhibited better diastereoselectivity compared to their C5-substituted counterparts. Moreover, both electron-rich and electron-deficient substituents on the aryl moiety of the enone were well-tolerated, consistently yielding products with high diastereoselectivity. Additionally, heteroaryl substituent, such as 2-furyl (2m), on the enone substrate also participated effectively in the cycloaddition reaction. This produced the corresponding benzosultam-fused tetrahydroquinazoline product 3am in 81% yield and an excellent diastereomeric ratio of >20:1. The relative stereochemistry of benzosultam-fused tetrahydroquinazolines 3 was determined by using two-dimensional NMR (¹H–¹H NOESY of 3aa; see Supporting Information). Correlations were observed between H-7 and H_s of the ethoxy group in the minor diastereomer, while no such correlation was detected in the major diastereomer. The configurations of the other products were assigned by analogy.

Scheme 3 Substrate scope of cyclic N-sulfonyl ketimines. Reagents and conditions: 1 (0.20 mmol), 2a (0.30 mmol), K₂CO₃ (0.040 mmol), EtOAc (2.0 mL), r.t. Isolated yield after chromatographic purification is reported. Diastereomeric ratio was determined by ¹H NMR analysis of the crude product.

Continuing our investigation into the versatility of the reaction, we explored the impact of various cyclic N-sulfonyl ketimines 1 by reacting them with 2-aminophenyl enone 2a (Scheme [3]). The results demonstrated that the reaction tolerates a wide range of substituents on the aromatic ring, irrespective of their electronic nature or position. Substituents such as Me (2b and 2c), MeO (2d), F (2e and 2f), Cl (2g), CF₃ (2h), and OCF₃ (2i) were all well-suited to the reaction, consistently yielding products with outstanding diastereoselectivities (overall >20:1 dr). Among these, the methyl-substituted cyclic N-sulfonyl ketimine (2c) stood out, delivering the desired benzosultam-fused tetrahydroquinazoline 3ca in excellent yield (99%) and impressive diastereoselectivity (>20:1 dr). These findings underscore the broad applicability and efficiency of the developed [4+2]-cycloaddition methodology.

To showcase the practicality of this [4+2]-cycloaddition reaction, a one-mmol-scale reaction was conducted using cyclic N-sulfonyl ketimine 1a and 2-aminophenyl enone 2a under the optimized conditions. This scale-up yielded the desired product 3aa in an excellent 92% yield and 16:1 dr (Scheme [4a]). Furthermore, the synthetic versatility of the benzosultam-fused tetrahydroquinazoline 3aa was demonstrated through subsequent transformations (Scheme [4b]). The carbonyl group within the tetrahydroquinazoline framework proved to be a versatile functional handle, enabling the synthesis of diverse derivatives. For instance, treatment of 3aa with the Tebbe reagent resulted in the formation of the corresponding alkene product 4 in 82% yield. Additionally, reaction of 3aa with p-toluenesulfonyl hydrazide proceeded smoothly, yielding the hydrazone derivative 5 in 74% yield.

Scheme 4 Synthetic utility

Scheme 5 Proposed reaction mechanism

On the basis of the relative configuration of benzosultam-fused tetrahydroquinazolines 3, we propose a tentative mechanistic and stereochemical rationale for this transformation (Scheme [5]). We suggest that the base deprotonates 2-aminophenyl enone 2a, generating the amide salt I. As shown in intermediate II, the nitrogen anion in I then initiates a nucleophilic attack on the imine moiety of 1a, followed by an aza-Michael reaction. These concerted steps lead to the formation of intermediate III. The catalytic cycle is completed through rapid proton transfer from the protonated base ion to the resulting enolate.

In summary, we have successfully developed a highly efficient and stereoselective cycloaddition of cyclic N-sulfonyl ketimines with 2-aminophenyl enones, catalyzed by K₂CO₃. This approach offers a straightforward and effective method for synthesizing a diverse range of structurally intricate and highly functionalized benzosultam-fused tetrahydroquinazolines bearing a quaternary carbon center, achieving high yields and excellent diastereoselectivities.

All reactions were performed using flame- or oven-dried glassware under an atmosphere of anhydrous nitrogen. Organic solvents were distilled prior to use. Organic solutions were concentrated under reduced pressure using a rotary evaporator. Chromatographic purification of products was accomplished using forced-flow chromatography on ICN 60 32–64 mesh silica gel 63. TLC was performed on EM Reagents 0.25 mm silica gel 60-F plates. Developed chromatograms were visualized by fluorescence quenching and with anisaldehyde stain. ¹H (400 MHz) and ¹³C{¹H} (100 MHz) spectra were internally referenced to the residual protic solvent signals. IR spectra were recorded on an FT-IR spectrometer. HRMS was carried out on a Q-TOF-MS with ESI using an electron impact ionization (EI-magnetic sector) mass spectrometer. Cyclic N-sulfonyl ketamine[8] and 2-aminophenyl enones[7a] [9] were prepared according to literature procedures.

[4+2]-Cycloaddition of Cyclic N-Sulfonyl Ketimines with 2-Aminophenyl Enones; General Procedure

To a 0.10 M solution of cyclic N-sulfonyl ketimine 1 (0.20 mmol, 1.0 equiv) and 2-aminophenyl enone 2 (0.30 mmol, 1.5 equiv) in EtOAc (2.0 mL) was added K₂CO₃ (0.040 mmol, 20 mol%) at r.t. The reaction mixture was stirred at the same temperature until cyclic N-sulfonyl ketimine 1 was completely consumed, as determined by TLC. Then, the reaction mixture was filtered through a plug of Celite. The crude filtrate was evaporated and the diastereoselectivity was calculated by using ¹H NMR analysis. The reaction mixture was purified by flash column chromatography (silica gel, EtOAc/hexanes) to afford the desired product 3.

Ethyl (7R,12aS)-7-(2-Oxo-2-phenylethyl)-7,12-dihydro-12aH-benzo[4,5]isothiazolo[3,2-b]quinazoline-12a-carboxylate 5,5-Dioxide (3aa)

Yield: 79 mg (85%); >20:1 dr; white solid; mp 86–88 °C; R_f = 0.3 (EtOAc/hexanes 4:6).

IR (neat): 3450, 1738, 1681, 1480, 1448, 1302, 1236, 1226, 1175, 1160, 1135, 1121, 1061, 1033 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.01–7.90 (m, 2 H), 7.78 (dt, J = 7.6, 1.0 Hz, 1 H), 7.68–7.62 (m, 2 H), 7.61–7.51 (m, 2 H), 7.49–7.40 (m, 2 H), 7.17–7.10 (m, 1 H), 7.05 (td, J = 7.7, 1.5 Hz, 1 H), 6.80 (td, J = 7.5, 1.2 Hz, 1 H), 6.71 (dd, J = 8.0, 1.2 Hz, 1 H), 5.98–5.89 (m, 1 H), 5.19 (s, 1 H), 4.10 (ddq, J = 37.3, 10.8, 7.1 Hz, 2 H), 3.91 (dd, J = 17.8, 5.3 Hz, 1 H), 3.56 (dd, J = 17.8, 6.9 Hz, 1 H), 1.07 (t, J = 7.1 Hz, 3 H).

¹³C{¹H} NMR (101 MHz, CDCl₃): δ = 196.4, 170.0, 139.2, 136.7, 135.6, 133.9, 133.8, 133.4, 131.3, 128.7, 128.4, 128.2, 126.7, 123.2, 122.8, 122.0, 121.2, 117.0, 74.1, 63.3, 46.7, 46.2, 13.9.

HRMS (EI): m/z [M]⁺ calcd for C₂₅H₂₂N₂O₅S: 462.1249; found: 462.1232.

Ethyl (7R,12aS)-10-Methoxy-7-(2-oxo-2-phenylethyl)-7,12-dihydro-12aH-benzo[4,5]isothiazolo[3,2-b]quinazoline-12a-carboxylate 5,5-Dioxide (3ab)

Yield: 81 mg (82%); 12:1 dr; white solid; mp 99–101 °C; R_f = 0.3 (EtOAc/hexanes 4:6).

IR (neat): 3353, 2978, 2903, 1738, 1683, 1488, 1449, 1304, 1243, 1174, 1129, 1062, 1031 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.00–7.91 (m, 2 H), 7.80 (dt, J = 7.6, 0.9 Hz, 1 H), 7.69–7.54 (m, 4 H), 7.49–7.41 (m, 2 H), 7.04 (d, J = 8.6 Hz, 1 H), 6.38 (dd, J = 8.6, 2.5 Hz, 1 H), 6.27 (d, J = 2.5 Hz, 1 H), 5.88 (dd, J = 7.0, 5.1 Hz, 1 H), 5.17 (s, 1 H), 4.21–4.04 (m, 2 H), 3.87 (dd, J = 17.8, 5.2 Hz, 1 H), 3.67 (s, 3 H), 3.54 (dd, J = 17.7, 7.1 Hz, 1 H), 1.09 (t, J = 7.1 Hz, 3 H).

¹³C{¹H} NMR (101 MHz, CDCl₃): δ = 196.6, 170.1, 159.7, 140.3, 136.7, 135.5, 133.9, 133.8, 133.4, 131.4, 128.8, 128.2, 127.8, 122.7, 122.0, 115.4, 107.3, 102.0, 73.9, 63.4, 55.2, 46.6, 46.3, 13.9.

HRMS (EI): m/z [M]⁺ calcd for C₂₆H₂₄N₂O₆S: 492.1355; found: 492.1354.

Ethyl (7R,12aS)-9-Methoxy-7-(2-oxo-2-phenylethyl)-7,12-dihydro-12aH-benzo[4,5]isothiazolo[3,2-b]quinazoline-12a-carboxylate 5,5-Dioxide (3ac)

Yield: 78 mg (79%), >20:1 dr; white solid; mp 91–93 °C; R_f = 0.3 (EtOAc/hexanes 4:6).

IR (neat): 3322, 2978, 2923, 1738, 1682, 1505, 1449, 1304, 1241, 1176, 1128, 1063, 1034 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.01–7.94 (m, 2 H), 7.79 (dt, J = 7.6, 1.0 Hz, 1 H), 7.67– 7.54 (m, 4 H), 7.49–7.42 (m, 2 H), 6.77–6.70 (m, 2 H), 6.66 (dd, J = 8.7, 2.7 Hz, 1 H), 5.90 (dd, J = 7.1, 5.3 Hz, 1 H), 4.87 (s, 1 H), 4.12 (ttd, J = 10.8, 7.1, 3.6 Hz, 2 H), 3.92 (dd, J = 17.7, 5.3 Hz, 1 H), 3.67 (s, 3 H), 3.56 (dd, J = 17.8, 7.1 Hz, 1 H), 1.09 (t, J = 7.1 Hz, 3 H).

¹³C{¹H} NMR (101 MHz, CDCl₃): δ = 196.5, 170.0, 155.0, 136.7, 136.3, 134.6, 133.8, 133.5, 132.2, 131.2, 128.8, 128.2, 126.7, 123.1, 121.8, 120.0, 114.8, 111.7, 75.5, 63.4, 55.6, 47.6, 46.0, 13.9.

HRMS (EI): m/z [M]⁺ calcd for C₂₆H₂₄N₂O₆S: 492.1355; found: 492.1351.

Ethyl (7R,12aS)-10-Fluoro-7-(2-oxo-2-phenylethyl)-7,12-dihydro-12aH-benzo[4,5]isothiazolo[3,2-b]quinazoline-12a-carboxylate 5,5-Dioxide (3ad)

Yield: 83 mg (86%); 7:1 dr; white solid; mp 98–100 °C; R_f = 0.3 (EtOAc/hexanes 4:6).

IR (neat): 3347, 2979, 2904, 1740, 1683, 1620, 1488, 1449, 1306, 1243, 1177, 1160, 1133, 1120, 1063, 1036 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.00–7.91 (m, 2 H), 7.83 (dt, J = 7.5, 0.9 Hz, 1 H), 7.73–7.55 (m, 4 H), 7.46 (dd, J = 8.3, 7.0 Hz, 2 H), 7.12 (dd, J = 8.6, 5.9 Hz, 1 H), 6.51 (td, J = 8.5, 2.5 Hz, 1 H), 6.41 (dd, J = 9.8, 2.5 Hz, 1 H), 5.94–5.80 (m, 1 H), 5.18 (s, 1 H), 4.12 (ddq, J = 42.6, 10.8, 7.1 Hz, 2 H), 3.84 (dd, J = 17.7, 5.2 Hz, 1 H), 3.53 (dd, J = 17.7, 7.2 Hz, 1 H), 1.10 (t, J = 7.1 Hz, 3 H).

¹³C{¹H} NMR (101 MHz, CDCl₃): δ = 196.2, 170.0, 161.4 (d, J¹ = 245.4 Hz), 140.6, 140.5 (d, J³ = 11.0 Hz), 136.6, 135.5, 134.1, 133.6, 131.6, 128.5 (d, J³ = 9.7 Hz), 128.2, 122.6, 122.2, 118.7, 118.7, 107.9 (d, J² = 21.9 Hz), 103.4 (d, J² = 25.2 Hz), 73.7, 63.6, 46.4, 46.1, 13.9.

¹⁹F NMR (376 MHz, CDCl₃): δ = –113.6.

HRMS (EI): m/z [M]⁺ calcd for C₂₅H₂₁FN₂O₅S: 480.1155; found: 480.1148.

Ethyl (7R,12aS)-9-Fluoro-7-(2-oxo-2-phenylethyl)-7,12-dihydro-12aH-benzo[4,5]isothiazolo[3,2-b]quinazoline-12a-carboxylate 5,5-Dioxide (3ae)

Yield: 81 mg (84%); >20:1 dr; white solid; mp 87–89 °C; R_f = 0.3 (EtOAc/hexanes 4:6).

IR (neat): 3353, 2961, 2902, 1740, 1682, 1502, 1449, 1303, 1235, 1175, 1135, 1062, 1034 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.91–7.84 (m, 2 H), 7.72 (dt, J = 7.6, 1.0 Hz, 1 H), 7.63–7.46 (m, 4 H), 7.42–7.34 (m, 2 H), 6.85 (dd, J = 9.0, 2.8 Hz, 1 H), 6.71 (td, J = 8.5, 2.8 Hz, 1 H), 6.62 (dd, J = 8.8, 4.8 Hz, 1 H), 5.82 (dd, J = 7.2, 4.9 Hz, 1 H), 5.00 (s, 1 H), 4.15–3.97 (m, 2 H), 3.83 (dd, J = 18.0, 5.0 Hz, 1 H), 3.50 (dd, J = 18.0, 7.2 Hz, 1 H), 1.02 (t, J = 7.1 Hz, 3 H).

¹³C{¹H} NMR (101 MHz, CDCl₃): δ = 196.2, 169.9, 157.7 (d, J¹ = 240.4 Hz), 136.5, 135.7, 135.2 (d, J⁴ = 2.2 Hz), 134.01, 133.99, 133.6, 131.4, 128.8, 128.2, 125.8 (d, J³ = 7.3 Hz), 123.0, 122.0, 118.9 (d, J³ = 7.8 Hz), 115.5 (d, J² = 22.8 Hz), 113.6 (d, J² = 23.8 Hz), 74.8, 63.5, 46.9 (d, J⁴ = 1.5 Hz), 45.8, 13.9.

¹⁹F NMR (376 MHz, CDCl₃): δ = –121.2.

HRMS (EI): m/z [M]⁺ calcd for C₂₅H₂₁FN₂O₅S: 480.1155; found: 480.1152.

Ethyl (7R,12aS)-9-Chloro-7-(2-oxo-2-phenylethyl)-7,12-dihydro-12aH-benzo[4,5]isothiazolo[3,2-b]quinazoline-12a-carboxylate 5,5-Dioxide (3af)

Yield: 83 mg (83%); >20:1 dr; white solid; mp 94–96 °C; R_f = 0.3 (EtOAc/hexanes 4:6).

IR (neat): 3353, 2980, 2902, 1739, 1683, 1488, 1448, 1303, 1240, 1175, 1127, 1062, 1033 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.99–7.88 (m, 2 H), 7.77 (dt, J = 7.6, 1.0 Hz, 1 H), 7.69–7.54 (m, 4 H), 7.50–7.40 (m, 2 H), 7.16 (d, J = 2.3 Hz, 1 H), 6.98 (dd, J = 8.5, 2.4 Hz, 1 H), 6.64 (d, J = 8.6 Hz, 1 H), 5.89 (t, J = 6.1 Hz, 1 H), 5.29 (s, 1 H), 4.22–4.02 (m, 2 H), 3.89 (dd, J = 18.0, 5.4 Hz, 1 H), 3.52 (dd, J = 18.0, 6.8 Hz, 1 H), 1.07 (t, J = 7.1 Hz, 3 H).

¹³C{¹H} NMR (101 MHz, CDCl₃): δ = 196.0, 169.8, 137.8, 136.5, 135.5, 134.1, 133.6, 133.5, 131.4, 128.8, 128.5, 128.2, 126.6, 125.6, 124.6, 122.8, 122.0, 118.1, 74.0, 63.5, 46.4, 45.8, 13.9.

HRMS (EI): m/z [M]⁺ calcd for C₂₅H₂₁ClN₂O₅S: 496.0860; found: 496.0890.

Ethyl (7R,12aS)-10-Bromo-7-(2-oxo-2-phenylethyl)-7,12-dihydro-12aH-benzo[4,5]isothiazolo[3,2-b]quinazoline-12a-carboxylate 5,5-Dioxide (3ag)

Yield: 85 mg (79%); 3:1 dr; white solid; mp 197–199 °C; R_f = 0.3 (EtOAc/hexanes 4:6).

IR (neat): 3313, 2987, 2901, 1735, 1697, 1676, 1603, 1594, 1495, 1474, 1456, 1448, 1323, 1264, 1243, 1207, 1174, 1157, 1148, 1061, 1025 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.07–7.90 (m, 2 H), 7.88–7.77 (m, 1 H), 7.74–7.62 (m, 2 H), 7.63–7.52 (m, 2 H), 7.52–7.39 (m, 2 H), 7.05 (d, J = 8.2 Hz, 1 H), 6.93 (dd, J = 8.2, 1.9 Hz, 1 H), 6.87 (d, J = 1.9 Hz, 1 H), 5.85 (dd, J = 7.1, 5.2 Hz, 1 H), 5.09 (s, 1 H), 4.23–4.02 (m, 2 H), 3.90–3.78 (m, 1 H), 3.71 (s, 1 H), 3.52 (dd, J = 17.8, 7.1 Hz, 1 H), 1.10 (t, J = 7.1 Hz, 3 H).

¹³C{¹H} NMR (101 MHz, CDCl₃): δ = 196.0, 170.0, 140.3, 136.6, 135.6, 134.1, 133.7, 131.6, 128.9, 128.4, 128.2, 124.1, 122.6, 122.3, 122.2, 121.9, 119.4, 73.8, 67.2, 63.6, 46.6, 45.7, 13.9.

HRMS (EI): m/z [M]⁺ calcd for C₂₅H₂₁BrN₂O₅S: 540.0355; found: 540.0380.

Ethyl (7R,12aS)-9-Bromo-7-(2-oxo-2-phenylethyl)-7,12-dihydro-12aH-benzo[4,5]isothiazolo[3,2-b]quinazoline-12a-carboxylate 5,5-Dioxide (3ah)

Yield: 85 mg (78%); >20:1 dr; white solid; mp 107–109 °C; R_f = 0.3 (EtOAc/hexanes 4:6).

IR (neat): 3346, 2980, 2902, 1738, 1683, 1487, 1448, 1303, 1240, 1176, 1128, 1063, 1033 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.98–7.88 (m, 2 H), 7.78 (dt, J = 7.7, 1.0 Hz, 1 H), 7.71–7.52 (m, 4 H), 7.45 (dd, J = 8.4, 7.1 Hz, 2 H), 7.30 (d, J = 2.2 Hz, 1 H), 7.12 (dd, J = 8.5, 2.2 Hz, 1 H), 6.59 (d, J = 8.5 Hz, 1 H), 5.88 (t, J = 6.1 Hz, 1 H), 5.26 (s, 1 H), 4.10 (ddq, J = 47.5, 10.8, 7.1 Hz, 2 H), 3.88 (dd, J = 18.0, 5.6 Hz, 1 H), 3.51 (dd, J = 18.0, 6.7 Hz, 1 H), 1.07 (t, J = 7.1 Hz, 3 H).

¹³C{¹H} NMR (101 MHz, CDCl₃): δ = 195.9, 169.8, 138.3, 136.5, 135.5, 134.1, 133.6, 133.5, 131.5, 131.4, 129.4, 128.8, 128.2, 124.9, 122.8, 122.0, 118.4, 112.9, 73.9, 63.5, 46.3, 45.7, 13.9.

HRMS (EI): m/z [M]⁺ calcd for C₂₅H₂₁BrN₂O₅S: 540.0355; found: 540.0358.

Ethyl (7R,12aS)-7-[2-Oxo-2-(p-tolyl)ethyl]-7,12-dihydro-12aH-benzo[4,5]isothiazolo[3,2-b]quinazoline-12a-carboxylate 5,5-Dioxide (3ai)

Yield: 65 mg (69%); >20:1 dr; white solid; mp 97–99 °C; R_f = 0.3 (EtOAc/hexanes 4:6).

IR (neat): 3323,2978, 2902, 1739, 1682, 1596, 1488, 1303, 1228, 1176, 1159, 1122, 1062, 1034 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.99–7.84 (m, 2 H), 7.82 (dt, J = 7.4, 1.1 Hz, 1 H), 7.72–7.65 (m, 1 H), 7.65–7.57 (m, 2 H), 7.26–7.23 (m, 2 H), 7.14 (dt, J = 7.7, 1.1 Hz, 1 H), 7.07 (td, J = 7.7, 1.5 Hz, 1 H), 6.82 (td, J = 7.5, 1.2 Hz, 1 H), 6.72 (dd, J = 8.0, 1.2 Hz, 1 H), 5.92 (dd, J = 7.0, 5.2 Hz, 1 H), 5.08 (s, 1 H), 4.22–4.01 (m, 2 H), 3.87 (dd, J = 17.7, 5.3 Hz, 1 H), 3.54 (dd, J = 17.7, 7.0 Hz, 1 H), 2.40 (s, 3 H), 1.09 (t, J = 7.1 Hz, 3 H).

¹³C{¹H} NMR (101 MHz, CDCl₃): δ = 195.9, 170.2, 144.3, 139.1, 135.8, 134.3, 134.0, 133.9, 131.4, 129.5, 128.4, 128.4, 126.8, 123.4, 122.7, 122.1, 121.3, 117.0, 74.1, 63.4, 46.8, 46.1, 21.8, 13.9.

HRMS (EI): m/z [M]⁺ calcd for C₂₆H₂₄N₂O₅S: 476.1406; found: 476.1393.

Ethyl (7R,12aS)-7-[2-(4-Fluorophenyl)-2-oxoethyl]-7,12-dihydro-12aH-benzo[4,5]isothiazolo[3,2-b]quinazoline-12a-carboxylate 5,5-Dioxide (3aj)

Yield: 69 mg (72%), 11:1 dr; white solid; mp 98–100 °C; R_f = 0.3 (EtOAc/hexanes 4:6).

IR (neat): 3321, 2978, 2902, 1736, 1682, 1595, 1506, 1488, 1474, 1303, 1226, 1175, 1157, 1123, 1062, 1033 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.04–7.96 (m, 2 H), 7.84–7.78 (m, 1 H), 7.70–7.59 (m, 3 H), 7.10 (dtd, J = 19.6, 8.1, 1.8 Hz, 4 H), 6.83 (td, J = 7.5, 1.2 Hz, 1 H), 6.73 (dd, J = 8.0, 1.2 Hz, 1 H), 5.91 (t, J = 6.1 Hz, 1 H), 5.10 (s, 1 H), 4.21–4.03 (m, 2 H), 3.90 (dd, J = 17.7, 5.5 Hz, 1 H), 3.53 (dd, J = 17.7, 6.7 Hz, 1 H), 1.10 (t, J = 7.1 Hz, 3 H).

¹³C{¹H} NMR (101 MHz, CDCl₃): δ = 194.9, 170.0, 166.0 (d, J¹ = 255.2 Hz), 139.2, 135.6, 134.0 (d, J³ = 3.0 Hz), 133.2 (d, J³ = 3.0 Hz), 131.4, 131.0, 130.9, 128.5, 126.8, 123.3, 122.8, 122.1, 121.4, 117.1, 115.9 (d, J² = 21.9 Hz), 74.2, 63.4, 46.8, 46.1, 13.9.

¹⁹F NMR (376 MHz, CDCl₃): δ = –104.6.

HRMS (EI): m/z [M]⁺ calcd for C₂₅H₂₁FN₂O₅S: 480.1155; found: 480.1147.

Ethyl (7R,12aS)-7-[2-(4-Bromophenyl)-2-oxoethyl]-7,12-dihydro-12aH-benzo[4,5]isothiazolo[3,2-b]quinazoline-12a-carboxylate 5,5-Dioxide (3ak)

Yield: 84 mg (78%); 17:1 dr; white solid; mp 104–106 °C; R_f = 0.3 (EtOAc/hexanes 4:6).

IR (neat): 3322, 2977, 2902, 1737, 1682, 1488, 1304, 1240, 1176 1161, 1124, 1064, 1034 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.88–7.78 (m, 3 H), 7.72–7.56 (m, 5 H), 7.16–7.04 (m, 2 H), 6.83 (td, J = 7.6, 1.2 Hz, 1 H), 6.73 (dd, J = 8.0, 1.2 Hz, 1 H), 5.89 (t, J = 6.1 Hz, 1 H), 5.09 (s, 1 H), 4.24–4.02 (m, 2 H), 3.89 (dd, J = 17.7, 5.6 Hz, 1 H), 3.51 (dd, J = 17.7, 6.7 Hz, 1 H), 1.10 (t, J = 7.1 Hz, 3 H).

¹³C{¹H} NMR (101 MHz, CDCl₃): δ = 195.5, 170.0, 139.2, 135.6, 135.5, 134.0, 133.9, 132.1, 131.4, 129.8, 128.7, 128.6, 126.8, 123.2, 122.8, 122.1, 121.4, 117.1, 74.2, 63.4, 46.8, 46.1, 14.0.

HRMS (EI): m/z [M]⁺ calcd for C₂₅H₂₁BrN₂O₅S: 540.0355; found: 540.0380.

Ethyl (7R,12aS)-7-[2-(4-Chlorophenyl)-2-oxoethyl]-7,12-dihydro-12aH-benzo[4,5]isothiazolo[3,2-b]quinazoline-12a-carboxylate 5,5-Dioxide (3al)

Yield: 94 mg (93%); >20:1 dr; white solid; mp 100–102 °C; R_f = 0.3 (EtOAc/hexanes 4:6).

IR (neat): 3322, 2977, 2902, 1736, 1683, 1488, 1305, 1240, 1176, 1123, 1063, 1034 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.94–7.85 (m, 2 H), 7.79 (dt, J = 7.6, 1.0 Hz, 1 H), 7.70–7.57 (m, 3 H), 7.46–7.39 (m, 2 H), 7.15–7.02 (m, 2 H), 6.82 (td, J = 7.5, 1.2 Hz, 1 H), 6.72 (dd, J = 8.0, 1.2 Hz, 1 H), 5.90 (t, J = 6.1 Hz, 1 H), 5.14 (s, 1 H), 4.23–4.00 (m, 2 H), 3.90 (dd, J = 17.8, 5.6 Hz, 1 H), 3.52 (dd, J = 17.7, 6.6 Hz, 1 H), 1.10 (t, J = 7.1 Hz, 3 H).

¹³C{¹H} NMR (101 MHz, CDCl₃): δ = 195.4, 169.9, 139.9, 139.2, 135.5, 135.1, 133.95, 133.89, 131.4, 129.7, 129.1, 128.5, 126.7, 123.1, 122.8, 122.0, 121.3, 117.1, 74.2, 63.4, 46.7, 46.1, 13.9.

HRMS (EI): m/z [M]⁺ calcd for C₂₅H₂₁ClN₂O₅S: 496.0860; found: 496.0869.

Ethyl (7R,12aS)-7-[2-(Furan-2-yl)-2-oxoethyl]-7,12-dihydro-12aH-benzo[4,5]isothiazolo[3,2-b]quinazoline-12a-carboxylate 5,5-Dioxide (3am)

Yield: 73 mg (81%); >20:1 dr; pale yellow solid; mp 203–205 °C; R_f = 0.3 (EtOAc/hexanes 4:6).

IR (neat): 3353, 2980, 2901, 1736, 1669, 1494, 1457, 1309, 1239, 1157, 1139, 1123, 1065, 1023 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.88–7.79 (m, 1 H), 7.72–7.60 (m, 3 H), 7.57 (dd, J = 1.7, 0.8 Hz, 1 H), 7.27 (d, J = 0.8 Hz, 1 H), 7.17 (ddd, J = 7.7, 1.5, 0.7 Hz, 1 H), 7.12–7.05 (m, 1 H), 6.84 (td, J = 7.5, 1.2 Hz, 1 H), 6.72 (dd, J = 8.1, 1.2 Hz, 1 H), 6.55 (dd, J = 3.6, 1.7 Hz, 1 H), 5.88 (dd, J = 7.2, 5.6 Hz, 1 H), 5.04 (s, 1 H), 4.19 (qd, J = 7.1, 1.9 Hz, 2 H), 3.72 (dd, J = 17.3, 5.6 Hz, 1 H), 3.46 (dd, J = 17.3, 7.2 Hz, 1 H), 1.17 (t, J = 7.1 Hz, 3 H).

¹³C{¹H} NMR (101 MHz, CDCl₃): δ = 185.5, 170.1, 152.7, 146.5, 139.1, 135.8, 133.9, 131.4, 128.6, 127.0, 123.0, 122.7, 122.2, 121.4, 117.6, 117.1, 112.7, 73.9, 63.5, 46.4, 13.9.

HRMS (EI): m/z [M]⁺ calcd for C₂₃H₂₀N₂O₆S: 452.1042; found: 452.1012.

Ethyl (7R,12aS)-2-Methyl-7-(2-oxo-2-phenylethyl)-7,12-dihydro-12aH-benzo[4,5]isothiazolo[3,2-b]quinazoline-12a-carboxylate 5,5-Dioxide (3ba)

Yield: 76 mg (79%); >20:1 dr; white solid; mp 98–100 °C; R_f = 0.3 (EtOAc/hexanes 4:6).

IR (neat): 3346, 3337, 2979, 2903, 1739, 1682, 1594, 1487, 1475, 1447, 1300, 1224, 1158, 1119, 1059, 1033 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.00–7.92 (m, 2 H), 7.60–7.50 (m, 3 H), 7.48–7.40 (m, 3 H), 7.17–7.10 (m, 1 H), 7.04 (td, J = 7.6, 1.5 Hz, 1 H), 6.79 (td, J = 7.5, 1.2 Hz, 1 H), 6.70 (dd, J = 8.0, 1.2 Hz, 1 H), 5.93 (dd, J = 7.0, 5.1 Hz, 1 H), 5.17 (s, 1 H), 4.20–3.99 (m, 2 H), 3.91 (dd, J = 17.8, 5.2 Hz, 1 H), 3.57 (dd, J = 17.8, 7.0 Hz, 1 H), 2.40 (s, 3 H), 1.08 (t, J = 7.1 Hz, 3 H).

¹³C{¹H} NMR (101 MHz, CDCl₃): δ = 196.5, 170.1, 142.2, 139.3, 136.7, 134.8, 133.9, 133.4, 132.9, 128.7, 128.3, 128.2, 126.7, 123.3, 122.6, 121.9, 121.1, 116.9, 74.0, 63.2, 46.7, 46.2, 21.4, 13.9.

HRMS (EI): m/z [M]⁺ calcd for C₂₆H₂₄N₂O₅S: 476.1406; found: 476.1434.

Ethyl (7R,12aS)-3-Methyl-7-(2-oxo-2-phenylethyl)-7,12-dihydro-12aH-benzo[4,5]isothiazolo[3,2-b]quinazoline-12a-carboxylate 5,5-Dioxide (3ca)

Yield: 95 mg (99%); >20:1 dr; white solid; mp 95–97 °C; R_f = 0.3 (EtOAc/hexanes 4:6).

IR (neat): 3346, 3336, 2980, 2901, 1738, 1682, 1594, 1487, 1475, 1447, 1301, 1243, 1190, 1159, 1145, 1119, 1061 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.00–7.92 (m, 2 H), 7.67 (d, J = 7.9 Hz, 1 H), 7.59–7.52 (m, 1 H), 7.48–7.37 (m, 4 H), 7.13 (dt, J = 7.6, 1.1 Hz, 1 H), 7.05 (td, J = 7.6, 1.4 Hz, 1 H), 6.80 (td, J = 7.5, 1.2 Hz, 1 H), 6.71 (dd, J = 8.1, 1.2 Hz, 1 H), 5.91 (dd, J = 6.9, 5.1 Hz, 1 H), 5.11 (s, 1 H), 4.21–4.05 (m, 2 H), 3.89 (dd, J = 17.8, 5.2 Hz, 1 H), 3.56 (dd, J = 17.8, 7.0 Hz, 1 H), 2.46 (s, 3 H), 1.08 (t, J = 7.1 Hz, 3 H).

¹³C{¹H} NMR (101 MHz, CDCl₃): δ = 196.4, 170.3, 145.2, 139.2, 136.7, 135.9, 133.4, 132.2, 131.1, 128.7, 128.4, 128.2, 126.7, 123.2, 122.9, 121.8, 121.1, 116.9, 73.9, 63.3, 46.5, 46.2, 22.0, 13.9.

HRMS (EI): m/z [M]⁺ calcd for C₂₆H₂₄N₂O₅S: 476.1406; found: 476.1411.

Ethyl (7R,12aS)-2-Methoxy-7-(2-oxo-2-phenylethyl)-7,12-dihydro-12aH-benzo[4,5]isothiazolo[3,2-b]quinazoline-12a-carboxylate 5,5-Dioxide (3da)

Yield: 74 mg (75%); >20:1 dr; white solid; mp 101–103 °C; R_f = 0.3 (EtOAc/hexanes 4:6).

IR (neat): 3346, 3337, 2922, 1739, 1682, 1591, 1485, 1291, 1249, 1185, 1166, 1146, 1119, 1063, 1034, 1017 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.02–7.90 (m, 2 H), 7.71 (d, J = 8.6 Hz, 1 H), 7.60–7.52 (m, 1 H), 7.49–7.40 (m, 2 H), 7.14 (dt, J = 7.8, 1.1 Hz, 1 H), 7.11–7.02 (m, 3 H), 6.81 (td, J = 7.6, 1.2 Hz, 1 H), 6.71 (dd, J = 8.0, 1.2 Hz, 1 H), 5.89 (dd, J = 6.9, 5.2 Hz, 1 H), 5.09 (s, 1 H), 4.22–4.01 (m, 2 H), 3.93–3.83 (m, 4 H), 3.56 (dd, J = 17.8, 7.0 Hz, 1 H), 1.09 (t, J = 7.1 Hz, 3 H).

¹³C{¹H} NMR (101 MHz, CDCl₃): δ = 196.4, 170.2, 164.1, 139.1, 138.1, 136.7, 133.4, 128.8, 128.4, 128.2, 126.8, 125.7, 123.6, 123.4, 121.2, 117.7, 117.0, 107.2, 73.8, 63.4, 56.2, 46.7, 46.2, 13.9.

HRMS (EI): m/z [M]⁺ calcd for C₂₆H₂₄N₂O₆S: 492.1355; found: 492.1354.

Ethyl (7R,12aS)-2-Fluoro-7-(2-oxo-2-phenylethyl)-7,12-dihydro-12aH-benzo[4,5]isothiazolo[3,2-b]quinazoline-12a-carboxylate 5,5-Dioxide (3ea)

Yield: 68 mg (71%); >20:1 dr; white solid; mp 138–140 °C; R_f = 0.3 (EtOAc/hexanes 4:6).

IR (neat): 3352, 3337, 2979, 1739, 1683, 1595, 1487, 1478, 1309, 1238, 1170, 1119, 1062, 1033 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.03–7.88 (m, 2 H), 7.79 (dd, J = 8.5, 4.6 Hz, 1 H), 7.62–7.50 (m, 1 H), 7.50–7.39 (m, 2 H), 7.34 (dd, J = 7.8, 2.2 Hz, 1 H), 7.32–7.26 (m, 1 H), 7.17–7.12 (m, 1 H), 7.07 (td, J = 7.7, 1.5 Hz, 1 H), 6.83 (td, J = 7.6, 1.2 Hz, 1 H), 6.74 (dd, J = 8.0, 1.2 Hz, 1 H), 5.92 (t, J = 6.2 Hz, 1 H), 5.17 (s, 1 H), 4.25–3.99 (m, 2 H), 3.90 (dd, J = 17.8, 5.7 Hz, 1 H), 3.54 (dd, J = 17.8, 6.8 Hz, 1 H), 1.09 (t, J = 7.1 Hz, 3 H).

¹³C{¹H} NMR (101 MHz, CDCl₃): δ = 196.2, 169.6, 165.7 (d, J¹ = 256.7 Hz), 138.9 (d, J³ = 8.9 Hz), 138.8, 136.6, 133.5, 130.1 (d, J⁴ = 2.8 Hz), 128.8, 128.5, 128.2, 126.7, 124.4 (d, J³ = 9.7 Hz), 123.9, 121.6, 119.2 (d, J² = 23.9 Hz), 117.4, 110.5 (d, J² = 25.0 Hz), 63.6, 47.2, 45.8, 13.8.

¹⁹F NMR (376 MHz, CDCl₃): δ = –102.1.

HRMS (EI): m/z [M]⁺ calcd for C₂₅H₂₁FN₂O₅S: 480.1155; found: 480.1149.

Ethyl (7R,12aS)-4-Fluoro-7-(2-oxo-2-phenylethyl)-7,12-dihydro-12aH-benzo[4,5]isothiazolo[3,2-b]quinazoline-12a-carboxylate 5,5-Dioxide (3fa)

Yield: 68 mg (72%); >20:1 dr; white solid; mp 90–92 °C; R_f = 0.3 (EtOAc/hexanes 4:6).

IR (neat): 3346, 1740, 1682, 1608, 1596, 1488, 1471, 1448, 1312, 1259, 1235, 1176, 1137, 1111 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.00–7.88 (m, 2 H), 7.65 (td, J = 8.1, 4.8 Hz, 1 H), 7.59–7.52 (m, 1 H), 7.49–7.40 (m, 3 H), 7.21 (td, J = 8.2, 0.7 Hz, 1 H), 7.17–7.11 (m, 1 H), 7.06 (td, J = 7.6, 1.4 Hz, 1 H), 6.82 (td, J = 7.5, 1.2 Hz, 1 H), 6.73 (dd, J = 8.0, 1.2 Hz, 1 H), 5.93 (dd, J = 6.9, 5.5 Hz, 1 H), 5.21 (s, 1 H), 4.25–4.00 (m, 2 H), 3.90 (dd, J = 17.8, 5.5 Hz, 1 H), 3.54 (dd, J = 17.8, 6.9 Hz, 1 H), 1.09 (t, J = 7.1 Hz, 3 H).

¹³C{¹H} NMR (101 MHz, CDCl₃): δ = 196.3, 169.6, 156.0 (d, J¹ = 260.7 Hz), 138.9, 138.8, 136.6, 136.4 (d, J³ = 7.2 Hz), 133.5, 128.8, 128.6, 128.2, 126.7, 123.8, 122.0 (d, J² = 19.2 Hz), 121.5, 118.7 (d, J³ = 4.0 Hz), 118.3 (d, J² = 18.4 Hz), 117.3, 74.5, 63.6, 47.2, 45.7, 13.8.

¹⁹F NMR (376 MHz, CDCl₃): δ = –113.5.

HRMS (EI): m/z [M]⁺ calcd for C₂₅H₂₁FN₂O₅S: 480.1155; found: 480.1151.

Ethyl (7R,12aS)-4-Chloro-7-(2-oxo-2-phenylethyl)-7,12-dihydro-12aH-benzo[4,5]isothiazolo[3,2-b]quinazoline-12a-carboxylate 5,5-Dioxide (3ga)

Yield: 70 mg (70%); >20:1 dr; white solid; mp 159–161 °C; R_f = 0.3 (EtOAc/hexanes 4:6).

IR (neat): 3335, 1741, 1686, 1473, 1455, 1310, 1235, 1200, 1128, 1087, 1065, 1009 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.05–7.86 (m, 2 H), 7.66–7.50 (m, 4 H), 7.46 (t, J = 7.6 Hz, 2 H), 7.17 (d, J = 7.7 Hz, 1 H), 7.09 (td, J = 7.7, 1.5 Hz, 1 H), 6.85 (td, J = 7.5, 1.2 Hz, 1 H), 6.73 (dd, J = 8.0, 1.2 Hz, 1 H), 5.94 (dd, J = 6.9, 5.4 Hz, 1 H), 5.06 (s, 1 H), 4.22–4.03 (m, 2 H), 3.89 (dd, J = 17.7, 5.5 Hz, 1 H), 3.55 (dd, J = 17.6, 7.0 Hz, 1 H), 1.10 (t, J = 7.1 Hz, 3 H).

¹³C{¹H} NMR (101 MHz, CDCl₃): δ = 197.3, 173.9, 152.9, 144.2, 140.0, 136.9, 133.2, 130.4, 129.0, 128.7, 128.5, 128.2, 127.2, 126.9, 123.9, 123.1, 121.4, 116.2, 108.3, 73.6, 62.0, 53.1, 45.9, 26.4, 14.2.

HRMS (EI): m/z [M]⁺ calcd for C₂₅H₂₁ClN₂O₅S: 496.0860; found: 496.0832.

Ethyl (7R,12aS)-7-(2-Oxo-2-phenylethyl)-2-(trifluoromethyl)-7,12-dihydro-12aH-benzo[4,5]isothiazolo[3,2-b]quinazoline-12a-carboxylate 5,5-Dioxide (3ha)

Yield: 70 mg (67%); >20:1 dr, white solid; mp 164–166 °C; R_f = 0.3 (EtOAc/hexanes 3:7).

IR (neat): 3327, 2964, 2922, 1740, 1682, 1596, 1495, 1449, 1311, 1262, 1243, 1171, 1122, 1061, 1031 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.00–7.82 (m, 5 H), 7.61–7.52 (m, 1 H), 7.52–7.41 (m, 2 H), 7.21–7.07 (m, 2 H), 6.87 (td, J = 7.5, 1.2 Hz, 1 H), 6.78 (dd, J = 8.0, 1.1 Hz, 1 H), 5.94 (t, J = 6.2 Hz, 1 H), 5.14 (s, 1 H), 4.26–4.02 (m, 2 H), 3.92 (dd, J = 17.9, 5.9 Hz, 1 H), 3.54 (dd, J = 17.9, 6.6 Hz, 1 H), 1.08 (t, J = 7.1 Hz, 3 H).

¹³C{¹H} NMR (101 MHz, CDCl₃): δ = 196.1, 169.5, 138.6, 137.6, 137.2, 136.6, 135.9 (q, J² = 33.4 Hz), 133.6, 128.8, 128.7, 128.6 (q, J³ = 3.5 Hz), 128.2, 126.8, 124.3, 123.0, 122.9 (q, J¹ = 273.4 Hz), 122.0, 120.5 (q, J³ = 3.8 Hz), 117.8, 74.5, 63.8, 47.4, 45.7, 13.8.

¹⁹F NMR (376 MHz, CDCl₃): δ = –62.8.

HRMS (EI): m/z [M]⁺ calcd for C₂₆H₂₁F₃N₂O₅S: 530.1123; found: 530.1150.

Ethyl (7R,12aS)-7-(2-Oxo-2-phenylethyl)-2-(trifluoromethoxy)-7,12-dihydro-12aH-benzo[4,5]isothiazolo[3,2-b]quinazoline-12a-carboxylate 5,5-Dioxide (3ia)

Yield: 84 mg (77%); >20:1 dr; white solid; mp 81–83 °C; R_f = 0.3 (EtOAc/hexanes 3:7).

IR (neat): 3347, 2964, 1740, 1683, 1596, 1485, 1448, 1309, 1246, 1210, 1172, 1138, 1118, 1062, 1032 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.95–7.84 (m, 2 H), 7.77 (dd, J = 8.4, 0.5 Hz, 1 H), 7.53–7.44 (m, 1 H), 7.42–7.33 (m, 4 H), 7.08 (ddd, J = 7.7, 1.5, 0.7 Hz, 1 H), 7.00 (td, J = 7.6, 1.5 Hz, 1 H), 6.77 (td, J = 7.5, 1.2 Hz, 1 H), 6.68 (dd, J = 8.0, 1.2 Hz, 1 H), 5.84 (t, J = 6.2 Hz, 1 H), 5.09 (s, 1 H), 4.04 (ddq, J = 43.8, 10.8, 7.1 Hz, 2 H), 3.83 (dd, J = 17.8, 5.8 Hz, 1 H), 3.46 (dd, J = 17.8, 6.7 Hz, 1 H), 1.00 (t, J = 7.1 Hz, 3 H).

¹³C{¹H} NMR (101 MHz, CDCl₃): δ = 196.1, 169.5, 152.9, 138.6 (two peaks overlapped), 136.6, 133.5, 132.4, 128.8, 128.6, 128.2, 126.8, 124.1(two peaks overlapped), 123.8, 121.8, 121.5 (q, J = 259.7 Hz), 117.6, 115.4, 74.2, 63.7, 47.4, 45.7, 13.8.

¹⁹F NMR (376 MHz, CDCl₃): δ = –57.8.

HRMS (EI): m/z [M]⁺ calcd for C₂₆H₂₁F₃N₂O₆S: 546.1072; found: 546.1066.

One-mmol-scale Synthesis of 3aa

To a solution of cyclic N-sulfonyl ketimine 1a (239 mg, 1.0 mmol) and 2-aminophenyl enone 2a (335 mg, 1.5 mmol) in EtOAc (10 mL, 0.10 M) was added K₂CO₃ (28 mg, 0.20 mmol) at r.t. The reaction mixture was stirred at the same temperature for 2 h and monitored by TLC. Then, the resulting mixture was filtered through a plug of Celite and concentrated in vacuo. The crude residue was purified by flash column chromatography (silica gel, EtOAc/hexane 2:3) to afford desired product 3aa; yield: 416 mg (92%); white solid.

Ethyl (7R,12aS)-7-(2-Phenylallyl)-7,12-dihydro-12aH-benzo[4,5]isothiazolo[3,2-b]quinazoline-12a-carboxylate 5,5-Dioxide (4)

A 0.5 M solution of Tebbe reagent in toluene (0.60 mL, 0.30 mmol) was added dropwise to a solution of 3aa (46 mg, 010 mmol) in THF (1.5 mL) at 0 °C. The reaction mixture was stirred for 2 h at r.t. Then, the resulting mixture was quenched with sat. aq NaHCO₃ solution and extracted with Et₂O. The combined organic layers were washed with brine, dried (anhydrous Na₂SO₄), and concentrated in vacuo. The crude residue was purified by flash column chromatography (silica gel, EtOAc/hexane 2:3) to afford desired product 4.

Yield: 38 mg (82%); yellow solid; mp 71–73 °C; R_f = 0.3 (EtOAc/hexanes 1:1).

IR (neat): 3350, 2981, 1739, 1488, 1301, 1273, 1238, 1174, 1161, 1135, 1122, 1049, 1022 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.88–7.75 (m, 1 H), 7.73–7.48 (m, 5 H), 7.49–7.37 (m, 2 H), 7.38–7.28 (m, 1 H), 7.06 (td, J = 7.6, 1.5 Hz, 1 H), 7.00 (dd, J = 7.4, 1.3 Hz, 1 H), 6.79 (td, J = 7.5, 1.2 Hz, 1 H), 6.69 (dd, J = 8.0, 1.2 Hz, 1 H), 5.43 (d, J = 1.3 Hz, 1 H), 5.14 (q, J = 1.2 Hz, 1 H), 5.02 (t, J = 7.1 Hz, 1 H), 4.97 (s, 1 H), 4.24 (qd, J = 7.1, 4.5 Hz, 2 H), 3.28 (ddd, J = 14.6, 6.6, 1.2 Hz, 1 H), 2.99 (ddd, J = 14.5, 7.6, 1.0 Hz, 1 H), 1.22 (t, J = 7.1 Hz, 3 H).

¹³C{¹H} NMR (101 MHz, CDCl₃): δ = 170.4, 144.4, 139.9, 138.8, 136.6, 133.9, 133.7, 131.3, 128.9, 128.3, 128.1, 127.5, 126.8, 122.9, 122.4, 122.1, 120.6, 117.1, 116.9, 116.6, 73.7, 63.5, 50.0, 43.2, 14.0.

HRMS (EI): m/z [M]⁺ calcd for C₂₆H₂₄N₂O₄S: 460.1457; found: 460.1460.

Ethyl (7R,12aS)-7-[(E)-2-Phenyl-2-(2-tosylhydrazineylidene)ethyl]-7,12-dihydro-12aH-benzo[4,5]isothiazolo[3,2-b]quinazoline-12a-carboxylate 5,5-Dioxide (5)

Compound 3aa (42 mg, 010 mmol) was added to a solution of p-toluenesulfonyl hydrazide (38 mg, 0.20 mmol) in MeOH (0.5 mL) at r.t. The reaction mixture was stirred at 60 °C in an oil bath for 96 h and monitored by TLC. Then, the resulting mixture was filtered through a plug of Celite. The filtrate was concentrated in vacuo. The crude residue was purified by flash column chromatography (silica gel, EtOAc/hexane 1:1) to afford desired product 5.

Yield: 47 mg (74%); white solid; mp 165–167 °C; R_f = 0.4 (EtOAc/hexanes 1:1).

IR (neat): 3334, 3171, 1728, 1690, 1495, 1458, 1349, 1315, 1247, 1185, 1167, 1138, 1086, 1049, 1038, 1026 cm^–1.

¹H NMR (400 MHz, Acetone): δ = 8.03–7.70 (m, 6 H), 7.68–7.51 (m, 2 H), 7.41 (qd, J = 3.8, 1.7 Hz, 3 H), 7.19 (dd, J = 14.0, 7.9 Hz, 3 H), 7.13–7.01 (m, 1 H), 6.86 (dt, J = 8.1, 1.4 Hz, 1 H), 6.78–6.63 (m, 1 H), 5.04 (dd, J = 8.9, 5.3 Hz, 1 H), 4.42 (qt, J = 7.2, 3.7 Hz, 2 H), 3.78 (s, 1 H), 3.62 (ddd, J = 14.7, 5.3, 1.0 Hz, 1 H), 3.41 (dd, J = 14.7, 8.9 Hz, 1 H), 2.42 (s, 3 H), 1.28 (t, J = 7.1 Hz, 3 H).

¹³C{¹H} NMR (101 MHz, Acetone): δ = 210.0, 171.4, 152.8, 144.0, 141.6, 141.6, 137.5, 135.8, 134.9, 134.4, 132.4, 130.2, 130.0, 129.4, 129.2, 128.6, 128.2, 127.6, 124.6, 122.7, 120.9, 120.9, 117.1, 74.6, 69.2, 64.7, 49.4, 49.3, 35.6, 21.5, 14.3.

HRMS (EI): m/z [M]⁺ calcd for C₃₂H₃₀N₄O₆S₂: 630.1607; found: 630.1598.

References

References

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