Synthesis of Tricyclic Lactams from Heterocyclic Imines

Abstract

Starting from different heterocyclic imines, a large number of annulated tricyclic lactams were prepared in a two-step synthesis. First, methoxyamides with a phenyl ring in α- or β-position were generated. Finally, these substrates were converted to valero- and caprolactams, respectively, via intramolecular Friedel–Crafts cyclization in the presence of a Lewis acid. Additionally, effects of substituent groups at the phenyl ring in the electrophilic aromatic substitution were investigated.

Lactam systems are popular and widely used substructures due to their multifaceted possible uses.[ ¹ ] In view of their prevalence in biologically active compounds,[2] [3] [4] [5] [6] the development of methods to prepare these molecules is still in the focus of many investigations.[ ⁷ ] Based on these facts a range of synthetic routes were published.[ ⁸ ] Apart from that, articles dealing with a general access starting from imines, especially from cyclic imines, are extremely seldom, whereas syntheses of β-lactams are well studied.[ ⁹ ] On the other hand, synthetic routes involving several kinds of reactive N-acyliminium ions, which often play a dominant role in the environment of imines, are well known.[ ¹⁰ ] However, some of these methods feature several disadvantages such as harsh reaction conditions, costly and sensitive reagents, or long reaction times.[ ¹⁰ ]

Thus, cyclic imines are suitable starting materials for such a targeted synthetic pathway generating different types of new lactam structures due to their reactive C=N bond in the ring. In the recent past, we often took advantage of this property to form lactam structures.[ ¹¹ ] In combination with the addition of acyl chlorides, which was previously established in our group,[ ¹² ] an array of tricyclic lactams with an annulated phenyl ring based on cyclic imines was available in only two steps (Scheme [1]). The lactamization was completed by means of a Lewis acid as part of an intramolecular Friedel–Crafts cyclization. Bearing the isoquinoline skeleton, the target structures could attract a great deal of attention in the pharmacological field. Similar isoquinoline derivatives are known as receptor agonist[ ¹³ ] or anticonvulsant agent.[ ¹⁴ ]

Due to the high pharmacological activity of their corresponding amines, 2,5-dihydrothiazoles and -oxazoles were selected as applicable starting materials.[ ¹⁵ ] In this context, a large number of different substituents at the five-membered imine were investigated and offer the possibility to examine their effects in consecutive reactions.

The new two-step reaction sequence for preparing different classes of lactams is based on heterocyclic imines. The known precursor compounds 1, 2,5-dihydrothiazoles and 2,5-dihydrooxazole, were synthesized by a modified Asinger­ protocol in a multicomponent reaction.[16] [17] Choosing an α-chloroaldehyde, a second variable carbonyl compound, ammonia, and sodium hydrosulfide or water in dichloromethane, the monocyclic imines 1 were obtained in a one-pot reaction in good yields (up to 73%) (Scheme [2]).

In the first step of the described synthesis, the imines 1 were treated with acyl chlorides, which are characterized by a phenyl ring in the α- or β-position (Scheme [3]). The substitution pattern at the phenyl ring was selected considering directing effects on the aromatic substitution in the last step. Without isolation of the resulting hydrolysis-sensitive chloroamides, addition of methanol in the presence of triethylamine led to the racemic methoxyamides 2 and 3.

The described procedure affords the desired methoxyamides 2 and 3 in good to excellent yields of up to 99% after workup by column chromatography (Table 1). It should be noted in particular that the amides 2i and 3b, which belong to the class of oxazolidines, resulted in higher yields than the corresponding thiazolidine compounds 2c and 3a, respectively. Concerning the substituent at the phenyl ring, the best result was achieved with the unsubstituted substrate (i.e., 2a, 99%). Apart from that, a significant dependence of the yields on the substituents at the phenyl ring, the five-membered imine ring, or on the chain length of the acyl group cannot be noticed.

Table 1 Methoxyamides 2 and 3

Entry	Imine	Amide	X	R1	R2	R3	R4	R5	Yield (%)a
1	1a	2a	S	Me	Me	Me	Me	H	99
2	1a	2b	S	Me	Me	Me	Me	Me	49
3	1a	2c	S	Me	Me	Me	Me	OMe	61
4	1b	2d	S	–(CH2)5–		Me	Me	Me	65
5	1b	2e	S	–(CH2)5–		Me	Me	OMe	38
6	1c	2f	S	Me	Me	–(CH2)5–		OMe	72
7	1d	2g	S	–(CH2)5–		–(CH2)5–		Me	67
8	1d	2h	S	–(CH2)5–		–(CH2)5–		OMe	24
9	1e	2i	O	Me	Me	Me	Me	OMe	67
10	1a	3a	S	Me	Me	Me	Me	OMe	53
11	1e	3b	O	Me	Me	Me	Me	OMe	88

^a Isolated yields.

The next step of the synthetic strategy towards tricyclic lactams was initiated by treating the methoxyamides 2 and 3 with the Lewis acid aluminum trichloride (Scheme [4]). By elimination of the methoxy group, reactive N-acyl­iminium ions were generated. These intermediates are predestined to react with an aromatic compound.[ ¹⁰ ] In this manner, the methoxyamides were successfully converted to the six-membered valerolactams 4 in an intramolecular Friedel–Crafts cyclization. To extend the utility and to establish the diversity of this strategy, the procedure was also applied exemplary to the synthesis of the seven-membered­ caprolactams 6.

Following this synthetic route, the racemic lactams 4 and 6 resulted predominantly in high yields (up to ~100%) after workup by column chromatography in several cases (Table 2). It is worth mentioning that the lactams 4c, 4e, 4i, and 6a were obtained in pure form without any further purification. Unlike in the synthesis of all other lactams, we failed to obtain a good yield of the valerolactam 4d (8%).

Table 2 Lactams 4, 6, and Hydroxyamides 5

Entry	Amide	Lactam	X	R1	R2	R3	R4	R5	Yield (%)a
1	2a	4a	S	Me	Me	Me	Me	H	25 (31)b
2	2b	4b	S	Me	Me	Me	Me	Me	35 (43)b
3	2c	4c	S	Me	Me	Me	Me	OMe	75
4	2d	4d	S	–(CH2)5–		Me	Me	Me	8 (35)b
5	2e	4e	S	–(CH2)5–		Me	Me	OMe	~100
6	2f	4f	S	Me	Me	–(CH2)5–		OMe	69
7	2g	4g	S	–(CH2)5–		–(CH2)5–		Me	38 (27)b
8	2h	4h	S	–(CH2)5–		–(CH2)5–		OMe	85
9	2i	4i	O	Me	Me	Me	Me	OMe	97
10	3a	6a	S	Me	Me	Me	Me	OMe	94
11	3b	6b	O	Me	Me	Me	Me	OMe	~100

^a Isolated yields.

^b Yield of the respective hydroxyamide 5, which results as a by-product.

Analysis of all the crude products by ¹H NMR spectroscopy showed a single regioisomer of valero- and caprolactams 4 and 6. Due to steric hindrance, the substitution occurs only in the para position of the mentioned groups. These assumptions are based on the interpretation of the NMR data of 4 and 6 and are verified by the X-ray crystal structure determination of 4i (see below). As known, methyl and methoxy groups increase the rate of reaction due to their donating electron inductive and resonance effect, respectively. The conversion of the substrates 2c, 2e, and 2h with a methoxy group at the phenyl ring provided correspondingly higher yields (up to ~100%) in comparison with the compounds 2b, 2d, and 2g (up to 38%) containing a methyl group at the phenyl ring. Based on this knowledge, an activated aromatic compound (R⁵ = OMe) was systematically chosen in the case of the methoxy­amides 3 to achieve high yields. This goal was easily accomplished with the excellent yields of 94% (i.e., 6a) and ~100% (i.e., 6b).

Cyclization of the methoxyamides 2a, 2b, 2d, and 2g led to the hydroxyamides 5 as the by-product. In regard to the discussion above, this fact documents an insufficient activation of the phenyl rings for further substitution. Instead, the reactive N-acyliminium ions are quenched with water in the course of the aqueous purification forming the hydroxyamides 5. This fact gives an adequate explanation for the unsatisfactory yields in the reaction of the lactams 4a, 4b, 4d, and 4g.

Supplemental to the methoxy group, the methoxyamides 2 and 3 contain additional Lewis basic functional groups, such as an amide group and a sulfide or an ether group. This fact justifies the use of 2.5 equivalents of aluminum trichloride in order to separate the methoxy group completely.

As mentioned above, only a single regioisomer was found in the ¹H NMR spectra of the crude lactams 4 and 6. In the case of the racemic valerolactam 4i, single crystals could be obtained and the proposed structural features were established by X-ray analysis (Figure [1]).

The X-ray crystal structure determination of 4i verifies the postulated constitution and moreover proves the expected position of the relatively voluminous substituent at the phenyl ring due to steric hindrance. Consequently, the constitution of all other prepared lactams 4 and 6 was assigned by analogy comparing the NMR data with 4i.

In conclusion, we have presented a new two-step sequence for the synthesis of different types of lactams starting from the heterocyclic imines 1. Treating these precursors with an acyl chloride followed by addition of methanol, the methoxyamides 2 and 3 were obtained in up to quantitative yields. Finally, the desired lactamization was initiated by means of the Lewis acid aluminum trichloride. Via an intramolecular Friedel–Crafts cyclization, the annulated tricyclic valerolactams 4 and caprolactams 6 were obtained in good to excellent yields depending on the influence of the substituent at the phenyl ring. The constitution of the lactams 4 and 6 was clarified by a single-crystal X-ray structure analysis of a selected valerolactam 4.

Synthetic procedures under argon atmosphere were performed on a vacuum line using standard Schlenk techniques. Preparative column chromatography was carried out using Grace SiO₂ (0.035–0.070 mm, type KG 60). TLC was performed on Merck SiO₂ F254 plates on aluminum sheets. Melting points were obtained on a melting point apparatus of Laboratory Devices and are uncorrected. ¹H and ¹³C NMR spectra were recorded on a Bruker AMX R 500 (measuring frequency: ¹H NMR = 500.1 MHz, ¹³C NMR = 125.8 MHz) or a Bruker Avance III 500 (measuring frequency: ¹H NMR = 499.9 MHz, ¹³C NMR = 125.7 MHz) spectrometer in CDCl₃ solution. As an internal standard, the residual signal was used [7.26 ppm (¹H NMR), 77.16 ppm (¹³C NMR)].[ ¹⁹ ] Assignments of the signals were supported by measurements applying DEPT and COSY techniques. The abbreviation n.r. in the ¹H NMR spectral data of 3b (2 ×) and 4f (1 ×) denotes not resolved. Mass spectra were obtained on a Finnigan-MAT 95 mass spectrometer with isobutane as the reagent gas. The IR spectra were recorded with a Bruker Tensor­ 27 spectrometer equipped with a ‘Golden Gate’ diamond-ATR (attenuated total reflection) unit. 2-Phenylacetyl chloride­,[ ²⁰ ] 2-(3-methylphenyl)acetyl chloride,[ ²¹ ] 2-(3-methoxyphenyl)acetyl chloride,[ ²² ] 2,2,5,5-tetramethyl-2,5-dihydro­thiazole (1a),[ ²³ ] 2,2-dimethyl-1-thia-4-azaspiro[4.5]dec-3-ene (1b),[ ²⁴ ] 2,2-dimethyl-1-thia-3-azaspiro[4.5]dec-3-ene (1c),[ ²⁵ ] 7-thia-14-azadispiro[5.1.5⁸.2⁶]pentadec-14-ene (1d),[ ²⁶ ] and 2,2,5,5-tetramethyl-2,5-di­hydro-oxazole (1e)[ ¹⁷ ] were prepared according to published procedures. CH₂Cl₂ was refluxed with CaH₂ and freshly distilled prior to use. MeOH was refluxed with Mg and freshly distilled prior to use. Et₃N was dried over molecular sieves and freshly distilled prior to use.

Methoxyamides 2 and 3; General Procedure A (GP A)

Under argon atmosphere, the respective imine 1 (1 equiv), dissolved in anhyd CH₂Cl₂ (2 mL per mmol imine), was cooled down to 0–5 °C. A solution of the respective acyl chloride (1.1 equiv) in anhyd CH₂Cl₂ (3 mL per mmol imine) was added dropwise. After stirring for 5 h at r.t., a solution of anhyd MeOH (3.7 equiv) and anhyd Et₃N (1.75 equiv) in anhyd CH₂Cl₂ (2 mL per mmol imine) was added dropwise at 0–5 °C. After stirring overnight at r.t., the solution was poured into ice-water (7 mL per mmol imine). The phases were separated and the aqueous phase was extracted with CH₂Cl₂ (3 × 4 mL per mmol imine). The combined organic phases were washed with sat. aq NaHCO₃ (1 × 4 mL per mmol imine), H₂O (1 × 4 mL per mmol imine), and dried (MgSO₄). The solvent was removed on a rotary evaporator. The crude product was purified as described below for individual cases.

(RS)-1-(4-Methoxy-2,2,5,5-tetramethyl-1,3-thiazolidin-3-yl)-2-phenylethan-1-one (2a)

Following GP A, dihydrothiazole 1a (320 mg, 2.24 mmol), 2-phenylacetyl chloride (380 mg, 2.46 mmol), anhyd MeOH (261 mg, 330 μL, 8.14 mmol), and anhyd Et₃N (411 mg, 563 μL, 4.07 mmol) were used. The crude product was purified by column chromatography (silica gel; n-hexane–MTBE, 4:1); yield: 647 mg (99%); colorless, extremely viscous oil; R_f  = 0.24 (n-hexane–MTBE, 4:1).

IR (ATR): 2979, 2931, 2827, 1654, 1604, 1584, 1496, 1454, 1387, 1367, 1264, 1210, 1195, 1165, 1140, 1080, 923, 718, 696 cm^–1.

¹H NMR (500.1 MHz, CDCl₃): δ = 1.04, 1.32, 1.83, 1.91 [4 s, 12 H, 2 × C(CH₃)₂], 3.50 (s, 3 H, OCH₃), 3.82 (d, ² J = 15.8 Hz, 1 H, CH₂), 3.85 (d, ² J = 15.6 Hz, 1 H, CH₂), 4.87 (s, 1 H, NCH), 7.24–7.26 (m, 3 H, 2 × o-CH_Ar, p-CH_Ar), 7.31–7.34 (m, 2 H, m-CH_Ar).

¹³C NMR (125.8 MHz, CDCl₃): δ = 23.3, 30.4, 30.9, 31.7 [2 × C(CH₃)₂], 44.6 (CH₂), 52.9 [C(CH₃)₂CH], 56.1 (OCH₃), 72.6 [C(CH₃)₂N], 99.3 (NCH), 127.3 (p-CH_Ar), 128.9, 128.9 (2 × o-CH_Ar, 2 × m-CH_Ar), 134.8 (C_Ar), 170.4 (C=O).

MS (CI, isobutane): m/z (%) = 294.3 (84, [MH]⁺).

HRMS (CI, isobutane): m/z calcd for C₁₆H₂₄NO₂S⁺: 294.1528; found: 294.1526.

(RS)-1-(4-Methoxy-2,2,5,5-tetramethyl-1,3-thiazolidin-3-yl)-2-(3-methylphenyl)ethan-1-one (2b)

Following GP A, dihydrothiazole 1a (286 mg, 2.00 mmol), 2-(3-methylphenyl)acetyl chloride (371 mg, 2.20 mmol), anhyd MeOH (237 mg, 300 μL, 7.40 mmol), and anhyd Et₃N (354 mg, 485 μL, 3.50 mmol) were used. The crude product was purified by column chromatography (silica gel; n-hexane–EtOAc, 4:1); yield: 300 mg (49%); colorless, extremely viscous oil; R_f  = 0.43 (n-hexane–EtOAc­, 4:1).

IR (ATR): 2981, 2932, 2867, 2828, 1658, 1610, 1592, 1490, 1467, 1449, 1388, 1368, 1270, 1213, 1197, 1167, 1142, 1081, 927, 765, 726, 695 cm^–1.

¹H NMR (500.1 MHz, CDCl₃): δ = 1.06, 1.33, 1.83, 1.92 [4 s, 12 H, 2 × C(CH₃)₂], 2.33 (s, 3 H, C_ArCH₃), 3.51 (s, 3 H, OCH₃), 3.78 (d, ² J = 15.9 Hz, 1 H, CH₂), 3.81 (d, ² J = 15.7 Hz, 1 H, CH₂), 4.88 (s, 1 H, NCH), 7.03–7.07 (m, 3 H, p-CH _ArCH₂, o-CH _ArCH₃, p-CH _ArCH₃), 7.20–7.23 (m, 1 H, m-CH_Ar).

¹³C NMR (125.8 MHz, CDCl₃): δ = 21.5 (C_Ar CH₃), 23.4, 30.4, 30.9, 31.7, [2 × C(CH₃)₂], 44.6 (CH₂), 52.9 [C(CH₃)₂CH], 56.1 (OCH₃), 72.6 [C(CH₃)₂N], 99.3 (NCH), 126.0, 128.0 (2 × CH_Ar), 128.8 (m-CH_Ar), 129.6 (CH_Ar), 134.7 (C _ArCH₂), 138.6 (C _ArCH₃), 170.6 (C=O).

MS (CI, isobutane): m/z (%) = 308.3 (100, [MH]⁺), 276.2 (46, [MH – CH₄O]⁺).

HRMS (CI, isobutane): m/z calcd for C₁₇H₂₆NO₂S⁺: 308.1684; found: 308.1684.

(RS)-1-(4-Methoxy-2,2,5,5-tetramethyl-1,3-thiazolidin-3-yl)-2-(3-methoxyphenyl)ethan-1-one (2c)

Following GP A, dihydrothiazole 1a (280 mg, 1.95 mmol), 2-(3-methoxyphenyl)acetyl chloride (397 mg, 2.15 mmol), anhyd MeOH (231 mg, 292 μL, 7.22 mmol), and anhyd Et₃N (345 mg, 473 μL, 3.41 mmol) were used. The crude product was purified by column chromatography (silica gel; n-hexane–MTBE, 7:3); yield: 385 mg (61%); yellow solid; mp 37–38 °C; R_f  = 0.32 (n-hexane–MTBE, 7:3).

IR (ATR): 3005, 2970, 2932, 2893, 2837, 2820, 1642, 1609, 1584, 1453, 1371, 1252, 1152, 1139, 1085, 925, 765, 720 cm^–1.

¹H NMR (500.1 MHz, CDCl₃): δ = 1.07, 1.33, 1.84, 1.93 [4 s, 12 H, 2 × C(CH₃)₂], 3.51 (s, 3 H, NCHOCH ₃), 3.79 (s, 3 H, C_ArOCH₃), 3.80, 3.84 (2 d, ² J = 15.2 Hz, 2 H, CH₂), 4.88 (s, 1 H, NCH), 6.80–6.85 (m, 3 H, p-CH _ArCH₂, o-CH _ArOCH₃, p-CH _ArOCH₃), 7.24–7.28 (m, 1 H, m-CH_Ar).

¹³C NMR (125.8 MHz, CDCl₃): δ = 23.3, 30.4, 30.9, 31.6 [2 × C(CH₃)₂], 44.7 (CH₂), 52.9 [C(CH₃)₂CH], 55.3 (C_ArOCH₃), 56.1 (NCHOCH₃), 72.6 [C(CH₃)₂N], 99.3 (NCH), 112.7 (p-CH_ArCH₂), 114.4 (o-CH_ArOCH₃), 121.2 (p-CH_ArOCH₃), 129.9 (m-CH_Ar), 136.3 (C _ArCH₂), 160.0 (C _ArOCH₃), 170.3 (C=O).

MS (CI, isobutane): m/z (%) = 324.1 (91, [MH]⁺), 292.1 (100, [MH – CH₄O]⁺).

HRMS (CI, isobutane): m/z calcd for C₁₇H₂₆NO₃S⁺: 324.1633; found: 324.1640.

(RS)-1-(3-Methoxy-2,2-dimethyl-1-thia-4-azaspiro[4.5]decan-4-yl)-2-(3-methylphenyl)ethan-1-one (2d)

Following GP A, dihydrothiazole 1b (367 mg, 2.00 mmol), 2-(3-methylphenyl)acetyl chloride (371 mg, 2.20 mmol), anhyd MeOH (237 mg, 300 μL, 7.40 mmol), and anhyd Et₃N (354 mg, 485 μL, 3.50 mmol) were used. The crude product was purified by column chromatography (silica gel; n-hexane–EtOAc, 4:1); yield: 448 mg (65%); colorless solid; mp 100 °C; R_f  = 0.49 (n-hexane–EtOAc, 4:1).

IR (ATR): 3020, 3007, 2984, 2965, 2926, 2861, 2851, 2821, 1661, 1625, 1609, 1591, 1492, 1464, 1455, 1384, 1366, 1271, 1259, 1244, 1179, 1144, 1086, 920, 778, 758, 720, 695 cm^–1.

¹H NMR (500.1 MHz, CDCl₃): δ = 1.04 [s, 3 H, C(CH₃)₂], 1.12–1.22, 1.27–1.36 (2 m, 2 H, CH_2,Cy), 1.32 [s, 3 H, C(CH₃)₂], 1.51–1.59 (m, 3 H, CH_2,Cy), 1.67–1.78 (m, 2 H, CH_2,Cy), 1.87–1.89 (m, 1 H, CH_2,Cy), 2.32 (s, 3 H, C_ArCH₃), 2.75–2.81, 3.17–3.22 (2 m, 2 H, CH_2,Cy), 3.49 (s, 3 H, OCH₃), 3.78 (d, ² J = 15.4 Hz, 1 H, CH₂C_Ar), 3.81 (d, ² J = 15.2 Hz, 1 H, CH₂C_Ar), 4.91 (s, 1 H, NCH), 7.02–7.06 (m, 3 H, p-CH _ArCH₂, o-CH _ArCH₂, p-CH _ArCH₃), 7.19–7.22 (m, 1 H, m-CH_Ar).

¹³C NMR (125.8 MHz, CDCl₃): δ = 21.5 (C_Ar CH₃), 23.5 [C(CH₃)₂], 24.6, 25.1, 25.9 (3 × CH_2,Cy), 30.4 [C(CH₃)₂], 36.7, 38.2 (2 × CH_2,Cy), 45.2 (CH₂C_Ar), 52.0 [C(CH₃)₂], 56.1 (OCH₃), 80.2 [C(CH_2,Cy)₅], 99.1 (NCH), 126.0, 127.9 (2 × CH_Ar), 128.8 (m-CH_Ar), 129.7 (CH_Ar), 134.8 (C _ArCH₂), 138.5 (C _ArCH₃), 170.9 (C=O).

MS (CI, isobutane): m/z (%) = 348.3 (54, [MH]⁺), 316.3 (100, [MH – CH₄O]⁺).

HRMS (CI, isobutane): m/z calcd for C₂₀H₃₀NO₂S⁺: 348.1997; found: 348.1990.

(RS)-1-(3-Methoxy-2,2-dimethyl-1-thia-4-azaspiro[4.5]decan-4-yl)-2-(3-methoxyphenyl)ethan-1-one (2e)

Following GP A, dihydrothiazole 1b (367 mg, 2.00 mmol), 2-(3-methoxyphenyl)acetyl chloride (406 mg, 2.20 mmol), anhyd MeOH (237 mg, 300 μL, 7.40 mmol), and anhyd Et₃N (354 mg, 485 μL, 3.50 mmol) were used. The crude product was purified by column chromatography (silica gel; n-hexane–MTBE, 9:1); yield: 278 mg (38%); colorless, extremely viscous oil; R_f  = 0.08 (n-hexane–MTBE, 9:1).

IR (ATR): 2930, 2857, 2834, 1654, 1600, 1585, 1491, 1453, 1439, 1386, 1367, 1299, 1254, 1165, 1140, 1083, 1049, 922, 767, 718, 691 cm^–1.

¹H NMR (500.1 MHz, CDCl₃): δ = 1.03 [s, 3 H, C(CH₃)₂], 1.13–1.21, 1.26–1.35 (2 m, 2 H, CH_2,Cy), 1.31 [s, 3 H, C(CH₃)₂], 1.51–1.59 (m, 3 H, CH_2,Cy), 1.69–1.78 (m, 2 H, CH_2,Cy), 1.86–1.88, 2.75–2.81, 3.17–3.21 (3 m, 3 H, CH_2,Cy), 3.49 (s, 3 H, NCHOCH ₃), 3.78 (d, ² J = 15.3 Hz, 1 H, CH₂C_Ar), 3.78 (s, 3 H, C_ArOCH₃), 3.82 (d, ² J = 15.3 Hz, 1 H, CH₂C_Ar), 4.90 (s, 1 H, NCH), 6.77–6.82 (m, 3 H, p-CH _ArCH₂, o-CH _ArOCH₃, p-CH _ArOCH₃), 7.21–7.24 (m, 1 H, m-CH_Ar).

¹³C NMR (125.8 MHz, CDCl₃): δ = 23.5 [C(CH₃)₂], 24.6, 25.1, 25.9 (3 × CH_2,Cy), 30.3 [C(CH₃)₂], 36.7, 38.2 (2 × CH_2,Cy), 45.3 (CH₂C_Ar), 52.0 [C(CH₃)₂], 55.3 (C_ArOCH₃), 56.1 (NCHOCH₃), 80.2 [C(CH_2,Cy)₅], 99.1 (NCH), 112.7 (p-CH_ArCH₂), 114.5 (o-CH_ArOCH₃), 121.3 (p-CH_ArOCH₃), 129.9 (m-CH_Ar), 136.4 (C _ArCH₂), 160.0 (C _ArOCH₃), 170.6 (C=O).

MS (CI, isobutane): m/z (%) = 364.2 (88, [MH]⁺), 332.2 (100, [MH – CH₄O]⁺).

HRMS (CI, isobutane): m/z calcd for C₂₀H₃₀NO₃S⁺: 364.1946; found: 364.1944.

(RS)-1-(4-Methoxy-2,2-dimethyl-1-thia-3-azaspiro[4.5]decan-3-yl)-2-(3-methoxyphenyl)ethan-1-one (2f)

Following GP A, dihydrothiazole 1c (367 mg, 2.00 mmol), 2-(3-methoxyphenyl)acetyl chloride (406 mg, 2.20 mmol), anhyd MeOH (237 mg, 300 μL, 7.40 mmol), and anhyd Et₃N (354 mg, 485 μL, 3.50 mmol) were used. The crude product was purified by column chromatography (silica gel; n-hexane–EtOAc, 4:1); yield: 522 mg (72%); colorless solid; mp 45 °C; R_f  = 0.33 (n-hexane–EtOAc, 4:1).

IR (ATR): 3001, 2971, 2929, 2852, 2834, 1638, 1610, 1583, 1488, 1456, 1435, 1378, 1353, 1282, 1183, 1166, 1148, 1076, 895, 773, 722 cm^–1.

¹H NMR (500.1 MHz, CDCl₃): δ = 1.07–1.32 (m, 5 H, CH_2,Cy), 1.41–1.44 (m, 1 H, CH_2,Cy), 1.51–1.67 (m, 4 H, CH_2,Cy), 1.84, 1.90 [2 s, 6 H, C(CH₃)₂], 3.50 (s, 3 H, NCHOCH ₃), 3.80 (d, ² J = 15.2 Hz, 1 H, CH₂C_Ar), 3.80 (s, 3 H, C_ArOCH₃), 3.85 (d, ² J = 15.2 Hz, 1 H, CH₂C_Ar), 4.96 (s, 1 H, NCH), 6.81–6.84 (m, 3 H, p-CH _ArCH₂, o-CH _ArOCH₃, p-CH _ArOCH₃), 7.24–7.28 (m, 1 H, m-CH_Ar).

¹³C NMR (125.8 MHz, CDCl₃): δ = 22.2, 24.4, 25.6 (3 × CH_2,Cy), 31.0, 32.1 [C(CH₃)₂], 33.2, 37.4 (2 × CH_2,Cy), 44.5 (CH₂C_Ar), 55.3 (C_ArOCH₃), 56.0 (NCHOCH₃), 59.1 [C(CH_2,Cy)₅], 71.6 [C(CH₃)₂], 98.6 (NCH), 112.7 (p-CH_ArCH₂), 114.4 (o-CH_ArOCH₃), 121.2 (p-CH_ArOCH₃), 129.9 (m-CH_Ar), 136.3 (C _Ar CH₂), 160.0 (C _ArOCH₃), 170.5 (C=O).

MS (CI, isobutane): m/z (%) = 364.4 (99, [MH]⁺), 332.3 (100, [MH – CH₄O]⁺).

HRMS (CI, isobutane): m/z calcd for C₂₀H₃₀NO₃S⁺: 364.1946; found: 364.1955.

(RS)-1-(15-Methoxy-7-thia-14-azadispiro[5.1.5⁸.2⁶]pentadecan-14-yl)-2-(3-methylphenyl)ethan-1-one (2g)

Following GP A, dihydrothiazole 1d (447 mg, 2.00 mmol), 2-(3-methylphenyl)acetyl chloride (371 mg, 2.20 mmol), anhyd MeOH (237 mg, 300 μL, 7.40 mmol), and anhyd Et₃N (354 mg, 485 μL, 3.50 mmol) were used. The crude product was purified by column chromatography twice (silica gel; 1. n-hexane–EtOAc, 7:3; 2. CH₂Cl₂–n-hexane, 4:1); yield: 516 mg (67%); colorless solid; mp 79–82 °C; R_f  = 0.73 (n-hexane–EtOAc, 7:3).

IR (ATR): 2929, 2856, 1657, 1610, 1591, 1491, 1451, 1372, 1273, 1254, 1179, 1081, 895, 764, 719, 694 cm^–1.

¹H NMR (500.1 MHz, CDCl₃): δ = 1.04–1.77 (m, 16 H, CH_2,Cy), 1.87–1.88 (m, 2 H, CH_2,Cy), 2.32 (s, 3 H, C_ArCH₃), 2.74–2.78, 3.16–3.20 (2 m, 2 H, CH_2,Cy), 3.47 (s, 3 H, OCH₃), 3.79–3.80 (m, 2 H, CH₂C_Ar), 4.98 (s, 1 H, NCH), 7.01–7.06 (m, 3 H, p-CH _ArCH₂, o-CH _ArCH₂, p-CH _ArCH₃), 7.19–7.22 (m, 1 H, m-CH_Ar).

¹³C NMR (125.8 MHz, CDCl₃): δ = 21.5 (C_Ar CH₃), 22.2, 24.3, 24.6, 25.0, 25.6, 25.8, 33.3, 37.1, 37.2, 38.2 (10 × CH_2,Cy), 45.0 (CH₂C_Ar), 56.0 (OCH₃), 58.0 [C(CH_2,Cy)₅CH], 79.1 [C(CH_2,Cy)₅N], 98.4 (NCH), 126.0, 127.9 (2 × CH_Ar), 128.7 (m-CH_Ar), 129.7 (CH_Ar), 134.8 (C _ArCH₂), 138.5 (C _ArCH₃), 171.0 (C=O).

MS (CI, isobutane): m/z (%) = 388.2 (33, [MH]⁺), 356.2 (100, [MH – CH₄O]⁺).

HRMS (CI, isobutane): m/z calcd for C₂₃H₃₄NO₂S⁺: 388.2310; found: 388.2301.

(RS)-1-(15-Methoxy-7-thia-14-azadispiro[5.1.5⁸.2⁶]pentadecan-14-yl)-2-(3-methoxyphenyl)ethan-1-one (2h)

Following GP A, dihydrothiazole 1d (447 mg, 2.00 mmol), 2-(3-methoxyphenyl)acetyl chloride (406 mg, 2.20 mmol), anhyd MeOH (237 mg, 300 μL, 7.40 mmol), and anhyd Et₃N (354 mg, 485 μL, 3.50 mmol) were used. The crude product was purified by column chromatography (silica gel; n-hexane–MTBE, 9:1); yield: 193 mg (24%); colorless, extremely viscous oil; R_f  = 0.08 (n-hexane–MTBE, 9:1).

IR (ATR): 2928, 2855, 1653, 1600, 1585, 1491, 1450, 1371, 1300, 1253, 1176, 1149, 1079, 1050, 893, 767, 729, 691 cm^–1.

¹H NMR (500.1 MHz, CDCl₃): δ = 1.01–1.77 (m, 16 H, CH_2,Cy), 1.86–1.88 (m, 2 H, CH_2,Cy), 2.74–2.78, 3.16–3.20 (2 m, 2 H, CH_2,Cy), 3.47 (s, 3 H, NCHOCH ₃), 3.78 (s, 3 H, C_ArOCH₃), 3.79 (d, ² J = 15.2 Hz, 1 H, CH₂C_Ar), 3.83 (d, ² J = 15.3 Hz, 1 H, CH₂C_Ar), 4.97 (s, 1 H, NCH), 6.78–6.82 (m, 3 H, p-CH _ArCH₂, o-CH _ArOCH₃, p-CH _ArOCH₃), 7.21–7.24 (m, 1 H, m-CH_Ar).

¹³C NMR (125.8 MHz, CDCl₃): δ = 22.2, 24.4, 24.6, 25.0, 25.6, 25.8, 33.3, 37.1, 37.2, 38.2 (10xCH_2,Cy), 45.2 (CH₂C_Ar), 55.4 (C_ArOCH₃), 56.1 (NCHOCH₃), 58.0 [C(CH_2,Cy)₅CH], 79.2 [C(CH_2,Cy)₅N], 98.5 (NCH), 112.7 (p-CH_ArCH₂), 114.5 (o-CH_ArOCH₃), 121.3 (p-CH_ArOCH₃), 129.9 (m-CH_Ar), 136.4 (C _ArCH₂), 160.0 (C _ArOCH₃), 170.6 (C=O).

MS (CI, isobutane): m/z (%) = 404.5 (24, [MH]⁺), 372.5 (100, [MH – CH₄O]⁺).

HRMS (CI, isobutane): m/z calcd for C₂₃H₃₄NO₃S⁺: 404.2259; found: 404.2263.

(RS)-1-(4-Methoxy-2,2,5,5-tetramethyl-1,3-oxazolidin-3-yl)-2-(3-methoxyphenyl)ethan-1-one (2i)

Following GP A, dihydrooxazole 1e (320 mg, 2.52 mmol), 2-(3-methoxyphenyl)acetyl chloride (511 mg, 2.77 mmol), anhyd MeOH (299 mg, 378 μL, 9.32 mmol), and anhyd Et₃N (446 mg, 611 μL, 4.41 mmol) were used. The crude product was purified by column chromatography (silica gel; n-hexane–EtOAc, 7:3); yield: 518 mg (67%); yellow, extremely viscous oil; R_f  = 0.21 (n-hexane–EtOAc, 7:3).

IR (ATR): 2982, 2938, 2835, 1660, 1600, 1585, 1491, 1455, 1437, 1392, 1373, 1256, 1196, 1163, 1075, 1049, 1004, 902, 771, 715, 691 cm^–1.

¹H NMR (500.1 MHz, CDCl₃): δ = 1.09, 1.33, 1.59, 1.63 [4 s, 12 H, 2 × C(CH₃)₂], 3.46 (s, 3 H, NCHOCH ₃), 3.72–3.72 (m, 2 H, CH₂), 3.79 (s, 3 H, C_ArOCH₃), 4.62 (s, 1 H, NCH), 6.79–6.85 (m, 3 H, p-CH _ArCH₂, o-CH _ArOCH₃, p-CH _ArOCH₃), 7.23–7.26 (m, 1 H, m-CH_Ar).

¹³C NMR (125.8 MHz, CDCl₃): δ = 22.9, 27.5, 27.5, 28.0 [2 × C(CH₃)₂], 43.0 (CH₂), 55.3 (C_ArOCH₃), 57.0 (NCHOCH₃), 81.9 [C(CH₃)₂CH], 94.0 (NCH), 95.5 [C(CH₃)₂N], 112.6 (p-CH_ArCH₂), 114.6 (o-CH_ArOCH₃), 121.3 (p-CH_ArOCH₃), 129.8 (m-CH_Ar), 136.3 (CH₂ C _Ar), 160.0 (C _ArOCH₃), 170.0 (C=O).

MS (CI, isobutane): m/z (%) = 308.2 (67, [MH]⁺), 276.2 (100, [MH – CH₄O]⁺).

HRMS (CI, isobutane): m/z calcd for C₁₇H₂₆NO₄ ⁺: 308.1862; found: 308.1855.

(RS)-1-(4-Methoxy-2,2,5,5-tetramethyl-1,3-thiazolidin-3-yl)-3-(3-methoxyphenyl)propan-1-one (3a)

Following GP A, dihydrothiazole 1a (287 mg, 2.00 mmol), 3-(3-methoxyphenyl)propanoyl chloride (437 mg, 2.20 mmol), anhyd MeOH (237 mg, 300 μL, 7.40 mmol), and anhyd Et₃N (354 mg, 485 μL, 3.50 mmol) were used. The crude product was purified by column chromatography (silica gel; n-hexane–EtOAc, 4:1); yield: 359 mg (53%); colorless, extremely viscous oil; R_f  = 0.38 (n-hexane–EtOAc, 4:1).

IR (ATR): 2962, 2933, 2865, 2833, 1656, 1601, 1584, 1489, 1465, 1454, 1438, 1388, 1376, 1260, 1165, 1151, 1080, 1051, 919, 779, 697 cm^–1.

¹H NMR (500.1 MHz, CDCl₃): δ = 1.36 [s, 6 H, C(CH₃)₂], 1.81, 1.91 [2 s, 6 H, C(CH₃)₂], 2.68–2.79 (m, 2 H, CH₂CO), 2.96–2.99 (m, 2 H, CH₂C_Ar), 3.39 (s, 3 H, NCHOCH ₃), 3.78 (s, 3 H, C_ArOCH₃), 4.82 (s, 1 H, NCH), 6.73–6.76 (m, 2 H, p-CH _ArCH₂, o-CH _ArOCH₃), 6.79–6.80 (m, 1 H, p-CH _ArOCH₃), 7.18–7.21 (m, 1 H, m-CH_Ar).

¹³C NMR (125.8 MHz, CDCl₃): δ = 23.4, 30.8, 30.9 [C(CH₃)₂], 31.7 (CH₂C_Ar), 32.1 [C(CH₃)₂], 38.5 (CH₂CO), 52.7 [C(CH₃)₂CH], 55.3 (C_ArOCH₃), 56.0 (NCHOCH₃), 72.7 [C(CH₃)₂N], 99.4 (NCH), 111.5 (p-CH_ArCH₂), 114.4 (o-CH_ArOCH₃), 120.9 (p-CH_ArOCH₃), 129.7 (m-CH_Ar), 142.7 (C _ArCH₂), 159.9 (C _ArOCH₃), 171.5 (C=O).

MS (CI, isobutane): m/z (%) = 338.3 (66, [MH]⁺), 306.2 (53, [MH – CH₄O]⁺).

HRMS (CI, isobutane): m/z calcd for C₁₈H₂₈NO₃S⁺: 338.1790; found: 338.1786.

(RS)-1-(4-Methoxy-2,2,5,5-tetramethyl-1,3-oxazolidin-3-yl)-3-(3-methoxyphenyl)propan-1-one (3b)

Following GP A, dihydrooxazole 1e (254 mg, 2.00 mmol), 3-(3-methoxyphenyl)propanoyl chloride (437 mg, 2.20 mmol), anhyd MeOH (237 mg, 300 μL, 7.40 mmol), and anhyd Et₃N (354 mg, 485 μL, 3.50 mmol) were used. The crude product was purified by column chromatography (silica gel; n-hexane–EtOAc, 7:3); yield: 565 mg (88%); colorless, extremely viscous oil; R_f  = 0.32 (n-hexane–EtOAc, 7:3).

IR (ATR): 2983, 2937, 2834, 1659, 1602, 1585, 1489, 1454, 1398, 1368, 1259, 1204, 1152, 1076, 1052, 1005, 900, 778, 696 cm^–1.

¹H NMR (500.1 MHz, CDCl₃): δ = 1.16, 1.33, 1.57, 1.61 [4 s, 12 H, 2 × C(CH₃)₂], 2.66–2.69 (m, 2 H, CH₂CO), 2.97–3.02 (m, 2 H, CH₂C_Ar), 3.37 (s, 3 H, NCHOCH ₃), 3.79 (s, 3 H, C_ArOCH₃), 4.51 (s, 1 H, NCH), 6.75 (dd, ³ J = 8.3 Hz, ⁴ J = 2.3 Hz, 1 H, p-CH _ArCH₂), 6.78 (d, ⁴ J = n.r., 1 H, o-CH _ArOCH₃), 6.82 (d, ³ J = 7.5 Hz, 1 H, p-CH _ArOCH₃), 7.21 (dd, ³ J = 7.8 Hz, ³ J = n.r., 1 H, m-CH_Ar).

¹³C NMR (125.8 MHz, CDCl₃): δ = 22.9, 27.7, 27.8, 27.9 [2 × C(CH₃)₂], 31.4 (CH₂C_Ar), 37.2 (CH₂CO), 55.3 (C_ArOCH₃), 56.9 (NCHOCH₃), 81.8 [C(CH₃)₂CH], 94.2 (NCH), 95.5 [C(CH₃)₂N], 111.6 (p-CH_ArCH₂), 114.4 (o-CH_ArOCH₃), 120.9 (p-CH_ArOCH₃), 129.7 (m-CH_Ar), 142.9 (C _ArCH₂), 159.9 (C _ArOCH₃), 171.0 (C=O).

MS (CI, isobutane): m/z (%) = 322.4 (66, [MH]⁺), 290.4 (100, [MH – CH₄O]⁺).

HRMS (CI, isobutane): m/z calcd for C₁₈H₂₈NO₄ ⁺: 322.2018; found: 322.2010.

Lactams 4 and 6; General Procedure B (GP B)

Under argon atmosphere, the respective methoxyamide (1 equiv), dissolved in anhyd CH₂Cl₂ (10 mL per mmol amide), was added dropwise to a suspension of AlCl₃ (2.5 equiv) in anhyd CH₂Cl₂ (7 mL per mmol amide) at 0–5 °C. After stirring for 2 h at r.t., the suspension was filtered. The filtrate was stirred overnight and then poured into ice-water (17 mL per mmol imine). The phases were separated and the aqueous phase was extracted with CH₂Cl₂ (3 × 20 mL per mmol imine). The combined organic phases were washed with aq NaOH (2 × 8 mL per mmol amide, 2%), H₂O (1 × 8 mL per mmol amide), and dried (MgSO₄). The solvent was removed on a rotary evaporator. The crude product was purified as described below for individual cases.

(RS)-1,1,3,3-Tetramethyl-6,10b-dihydro-3H-[1,3]thiazolo[4,3-a]isoquinolin-5-one (4a)

Following GP B, methoxyamide 2a (94 mg, 0.32 mmol) and AlCl₃ (107 mg, 0.80 mmol) were used. The crude product was purified by column chromatography (silica gel; n-hexane–MTBE, 7:3); yield: 20 mg (25%); colorless solid; mp 92–94 °C; R_f  = 0.28 (n-hexane–MTBE, 7:3).

IR (ATR): 3016, 2968, 2927, 2857, 1650, 1590, 1498, 1464, 1421, 1401, 1375, 1362, 1316, 1282, 1190, 1166, 1155, 1127, 760 cm^–1.

¹H NMR (500.1 MHz, CDCl₃): δ = 1.20, 1.65, 1.81, 2.09 [4 s, 12 H, 4 × CH₃], 3.56 (dd, ² J = 20.3 Hz, ⁵ J = 1.3 Hz, 1 H, CH₂), 3.85 (dd, ² J = 20.3 Hz, ⁵ J = 2.0 Hz, 1 H, CH₂), 4.98–4.99 (m, 1 H, NCH), 7.13–7.15 (m, 1 H, o-CH _ArCH₂), 7.23–7.30 (m, 2 H, p-CH _ArCH₂, p-CH _ArCH), 7.34–7.36 (m, 1 H, o-CH _ArCH).

¹³C NMR (125.8 MHz, CDCl₃): δ = 25.3, 26.6, 30.4, 32.2 (4 × CH₃), 38.7 (CH₂), 54.4 [C(CH₃)₂CH], 69.4 [C(CH₃)₂N], 72.7 (NCH), 125.8 (o-CH_ArCH), 126.5 (CH_Ar), 127.8 (o-CH_ArCH₂), 128.1 (CH_Ar), 130.0 (C _ArCH), 132.4 (C _ArCH₂), 167.1 (C=O).

MS (CI, isobutane): m/z (%) = 262.3 (100, [MH]⁺).

HRMS (CI, isobutane): m/z calcd for C₁₅H₂₀NOS⁺: 262.1266; found: 262.1262.

(RS)-1-(4-Hydroxy-2,2,5,5-tetramethyl-1,3-thiazolidin-3-yl)-2-phenylethan-1-one (5a)

By-product of 4a; yield: 29 mg (31%); colorless solid; mp 127–128 °C; R_f  = 0.13 (n-hexane–MTBE, 7:3).

IR (ATR): 3394, 2976, 2929, 1640, 1604, 1498, 1467, 1445, 1423, 1376, 1269, 1204, 1162, 1140, 1120, 1063, 745, 714, 697 cm^–1.

¹H NMR (500.1 MHz, CDCl₃): δ = 1.24, 1.31, 1.87, 1.95 (4 s, 12 H, 4 × CH₃), 2.94 (d, ³ J = 11.7 Hz, 1 H, OH), 3.86, 3.90 (2 d, ² J = 15.3 Hz, 2 H, CH₂), 5.11 (d, ³ J = 11.5 Hz, 1 H, NCH), 7.28–7.29 (m, 3 H, 2 × o-CH_Ar, p-CH_Ar), 7.34–7.37 (m, 2 H, 2 × m-CH_Ar).

¹³C NMR (125.8 MHz, CDCl₃): δ = 23.9, 29.5, 31.3, 31.9 (4 × CH₃), 44.3 (CH₂), 53.4 [C(CH₃)₂CH], 72.2 [C(CH₃)₂N], 92.4 (NCH), 127.1 (p-CH_Ar), 128.8, 128.9 (2 × o-CH_Ar, 2 × m-CH_Ar), 135.0 (C_Ar), 170.7 (C=O).

MS (CI, isobutane): m/z (%) = 280.3 (95, [MH]⁺), 262.3 (100, [MH – H₂O]⁺).

HRMS (CI, isobutane): m/z calcd for C₁₅H₂₂NO₂S⁺: 280.1371; found: 280.1375.

(RS)-1,1,3,3,8-Pentamethyl-6,10b-dihydro-3H-[1,3]thiazolo[4,3-a]isoquinolin-5-one (4b)

Following GP B, methoxyamide 2b (80 mg, 0.26 mmol) and AlCl₃ (87 mg, 0.65 mmol) were used. Analysis of the crude product by ¹H NMR spectroscopy showed a single regioisomer. The crude product was purified by column chromatography (silica gel; n-hexane–MTBE­, 7:3); yield: 26 mg (35%); colorless solid; mp 157–160 °C; R_f  = 0.30 (n-hexane–MTBE, 7:3).

IR (ATR): 2990, 2966, 2945, 2923, 2862, 1639, 1581, 1506, 1461, 1399, 1373, 1357, 1278, 1193, 1162, 1125, 944, 834, 787 cm^–1.

¹H NMR (500.1 MHz, CDCl₃): δ = 1.19, 1.64, 1.80, 2.08 [4 s, 12 H, 2 × C(CH₃)₂], 2.33 (s, 3 H, C_ArCH₃), 3.49–3.53 (m, 1 H, CH₂), 3.78–3.82 (m, 1 H, CH₂), 4.95–4.96 (m, 1 H, NCH), 6.94–6.95 (m, 1 H, o-CH _ArCH₂), 7.04–7.06 (m, 1 H, p-CH _ArCH₂), 7.23 (d, ³ J = 8.0 Hz, 1 H, o-CH _ArCH).

¹³C NMR (125.8 MHz, CDCl₃): δ = 21.1 (C_Ar CH₃), 25.2, 26.6, 30.4, 32.2 [2 × C(CH₃)₂], 38.7 (CH₂), 54.3 [C(CH₃)₂CH], 69.4 [C(CH₃)₂N], 72.6 (NCH), 125.6 (o-CH_ArCH), 127.1 (C _ArCH), 127.4 (p-CH_ArCH₂), 128.2 (o-CH_ArCH₂), 132.3 (C _ArCH₂), 137.9 (C _ArCH₃), 167.1 (C=O).

MS (CI, isobutane): m/z (%) = 276.3 (100, [MH]⁺).

HRMS (CI, isobutane): m/z calcd for C₁₆H₂₂NOS⁺: 276.1422; found: 276.1430.

(RS)-1-(4-Hydroxy-2,2,5,5-tetramethyl-1,3-thiazolidin-3-yl)-2-(3-methylphenyl)ethan-1-one (5b)

By-product of 4b; yield: 32 mg (43%); yellow solid; mp 117–119 °C; R_f  = 0.15 (n-hexane–MTBE, 7:3).

IR (ATR): 3417, 2998, 2980, 2963, 2929, 2868, 1639, 1611, 1593, 1491, 1466, 1445, 1374, 1270, 1246, 1205, 1163, 1141, 1118, 1060, 884, 766, 722 cm^–1.

¹H NMR (500.1 MHz, CDCl₃): δ = 1.24, 1.30, 1.85, 1.93 [4 s, 12 H, 2 × C(CH₃)₂], 2.33 (s, 3 H, C_ArCH₃), 2.83 (d, ³ J = 11.8 Hz, 1 H, OH), 3.80, 3.85 (2 d, ² J = 15.3 Hz, 2 H, CH₂), 5.10 (d, ³ J = 11.7 Hz, 1 H, NCH), 7.05–7.08 (m, 3 H, p-CH _ArCH₂, o-CH _ArCH₂, p-CH _ArCH₃), 7.20–7.23 (m, 1 H, m-CH_Ar).

¹³C NMR (125.8 MHz, CDCl₃): δ = 21.5 (C_Ar CH₃), 23.9, 29.6, 31.3, 31.9 [2 × C(CH₃)₂], 44.2 (CH₂), 53.4 [C(CH₃)₂CH], 72.2 [C(CH₃)₂N], 92.4 (NCH), 125.8, 127.9 (2 × CH_Ar), 128.8 (m-CH_Ar), 129.6 (CH_Ar), 134.9 (C _ArCH₂), 138.6 (C _ArCH₃), 170.8 (C=O).

MS (CI, isobutane): m/z (%) = 294.3 (22, [MH]⁺).

HRMS (CI, isobutane): m/z calcd for C₁₆H₂₄NO₂S⁺: 294.1528; found: 294.1525.

(RS)-8-Methoxy-1,1,3,3-tetramethyl-6,10b-dihydro-3H-[1,3]thiazolo[4,3-a]isoquinolin-5-one (4c)

Following GP B, methoxyamide 2c (102 mg, 0.32 mmol) and AlCl₃ (107 mg, 0.80 mmol) were used. Analysis of the crude product by ¹H NMR spectroscopy showed a single regioisomer. Purification was not necessary; yield: 70 mg (75%); yellow solid; mp 139–140 °C.

IR (ATR): 3015, 2964, 2917, 2856, 2827, 1652, 1612, 1508, 1464, 1444, 1427, 1401, 1293, 1256, 1247, 1224, 1157, 1031, 833, 793 cm^–1.

¹H NMR (500.1 MHz, CDCl₃): δ = 1.18, 1.62, 1.80, 2.07 [4 s, 12 H, 2 × C(CH₃)₂], 3.52 (dd, ² J = 20.4 Hz, ⁵ J = 1.3 Hz, 1 H, CH₂), 3.80 (s, 3 H, OCH₃), 3.80–3.84 (m, 1 H, CH₂), 4.92–4.93 (m, 1 H, NCH), 6.62 (d, ⁴ J = 2.3 Hz, 1 H, o-CH _ArCH₂), 6.80 (dd, ³ J = 8.7 Hz, ⁴ J = 2.5 Hz, 1 H, p-CH _ArCH₂), 7.25 (d, ³ J = 8.9 Hz, 1 H, m-CH _ArOCH₃).

¹³C NMR (125.8 MHz, CDCl₃): δ = 25.1, 26.6, 30.4, 32.2 [2 × C(CH₃)₂], 38.9 (CH₂), 54.3 [C(CH₃)₂CH], 55.4 (OCH₃), 69.4 [C(CH₃)₂N], 72.3 (NCH), 111.6 (o-CH_ArCH₂), 113.3 (p-CH_ArCH₂), 122.3 (C _ArCH), 127.0 (m-CH_ArOCH₃), 133.9 (C _ArCH₂), 159.2 (C _ArOCH₃), 167.0 (C=O).

MS (CI, isobutane): m/z (%) = 292.2 (100, [MH]⁺).

HRMS (CI, isobutane): m/z calcd for C₁₆H₂₂NO₂S⁺: 292.1371; found: 292.1364.

(RS)-1′,1′,8′-Trimethyl-6′,10b′-dihydrospiro[cyclohexane-1,3′-thiazolo[4,3-a]isoquinolin]-5′-one (4d)

Following GP B, methoxyamide 2d (90 mg, 0.26 mmol) and AlCl₃ (87 mg, 0.65 mmol) were used. Analysis of the crude product by ¹H NMR spectroscopy showed a single regioisomer. The crude product was purified by column chromatography (silica gel; n-hexane–EtOAc, 4:1); yield: 5 mg (8%); yellow, extremely viscous oil; R_f  = 0.41 (n-hexane–EtOAc, 4:1).

IR (ATR): 2925, 2855, 1656, 1510, 1459, 1447, 1428, 1404, 1290, 1128, 904, 823, 784 cm^–1.

¹H NMR (500.1 MHz, CDCl₃): δ = 1.15 [s, 3 H, C(CH₃)₂], 1.24–1.31 (m, 1 H, CH_2,Cy), 1.38–1.55 (m, 2 H, CH_2,Cy), 1.60–1.64 (m, 1 H, CH_2,Cy), 1.63 [s, 3 H, C(CH₃)₂], 1.75–1.87 (m, 3 H, CH_2,Cy), 1.98–2.00 (m, 1 H, CH_2,Cy), 2.33 (s, 3 H, C_ArCH₃), 2.36–2.42, 3.45–3.51 (2 m, 2 H, CH_2,Cy), 3.50–3.54 (m, 1 H, CH₂C_Ar), 3.82 (dd, ² J = 20.2 Hz, ⁵ J = 2.2 Hz, 1 H, CH₂C_Ar), 4.93–4.94 (m, 1 H, NCH), 6.94–6.95 (m, 1 H, o-CH _ArCH₂), 7.04–7.05 (m, 1 H, p-CH _ArCH₂), 7.21 (d, ³ J = 8.0 Hz, 1 H, o-CH _ArCH).

¹³C NMR (125.8 MHz, CDCl₃): δ = 21.1 (C_Ar CH₃), 24.1, 24.8 (2 × CH_2,Cy), 25.2 [C(CH₃)₂], 26.1 (CH_2,Cy), 26.7 [C(CH₃)₂], 37.6, 38.1 (2 × CH_2,Cy), 39.3 (CH₂C_Ar), 53.1 [C(CH₃)₂], 72.4 (NCH), 77.0 [C(CH_2,Cy)₅], 125.7 (o-CH_ArCH), 127.2 (C _ArCH), 127.4 (p-CH_ArCH₂), 128.1 (o-CH_ArCH₂), 132.1 (C _ArCH₂), 137.9 (C _ArCH₃), 167.4 (C=O).

MS (CI, isobutane): m/z (%) = 316.3 (100, [MH]⁺).

HRMS (CI, isobutane): m/z calcd for C₁₉H₂₆NOS⁺: 316.1735; found: 316.1738.

(RS)-1-(3-Hydroxy-2,2-dimethyl-1-thia-4-azaspiro[4.5]decan-4-yl)-2-(3-methylphenyl)ethan-1-one (5d)

By-product of 4d; yield: 31 mg (35%); colorless solid; mp 98–100 °C; R_f  = 0.21 (n-hexane–EtOAc, 4:1).

IR (ATR): 3269, 3014, 2984, 2926, 2858, 1625, 1607, 1589, 1487, 1448, 1404, 1373, 1180, 1167, 1154, 1134, 1077, 767, 720, 691 cm^–1.

¹H NMR (499.9 MHz, CDCl₃): δ = 1.20 [s, 3 H, C(CH₃)₂], 1.17–1.28 (m, 2 H, CH_2,Cy), 1.29 [s, 3 H, C(CH₃)₂], 1.54–1.78 (m, 6 H, CH_2,Cy), 2.32 (s, 3 H, C_ArCH₃), 2.85 (d, ³ J = 11.7 Hz, 1 H, OH), 3.00–3.12 (m, 2 H, CH_2,Cy), 3.80 (d, ² J = 15.4 Hz, 1 H, CH₂C_Ar), 3.84 (d, ² J = 15.3 Hz, 1 H, CH₂C_Ar), 5.13 (d, ³ J = 11.7 Hz, 1 H, NCH), 7.04–7.07 (m, 3 H, p-CH _ArCH₂, o-CH _ArCH₃, p-CH _ArCH₃), 7.19–7.22 (m, 1 H, m-CH_Ar).

¹³C NMR (125.7 MHz, CDCl₃): δ = 21.5 (C_Ar CH₃), 24.1 [C(CH₃)₂], 24.6, 25.4, 25.6 (3 × CH_2,Cy), 29.8 [C(CH₃)₂], 36.7, 39.8 (2 × CH_2,Cy), 44.9 (CH₂C_Ar), 52.5 [C(CH₃)₂], 80.1 [C(CH_2,Cy)₅], 92.3 (NCH), 125.9, 127.8 (2xCH_Ar), 128.8 (m-CH_Ar), 129.6 (CH_Ar), 135.1 (C _ArCH₂), 138.5 (C _ArCH₃), 171.0 (C=O).

MS (CI, isobutane): m/z (%) = 334.4 (100, [MH]⁺), 316.3 (44, [MH – H₂O]⁺).

HRMS (CI, isobutane): m/z calcd for C₁₉H₂₈NO₂S⁺: 334.1841; found: 334.1835.

(RS)-8′-Methoxy-1′,1′-Dimethyl-6′,10b′-dihydrospiro[cyclohexane-1,3′-thiazolo[4,3-a]isoquinolin]-5′-one (4e)

Following GP B, methoxyamide 2e (102 mg, 0.28 mmol) and AlCl₃ (94 mg, 0.70 mmol) were used. Analysis of the crude product by ¹H NMR spectroscopy showed a single regioisomer. Purification was not necessary; yield: 92 mg (100%); yellow solid; mp 121–123 °C.

IR (ATR): 2921, 2855, 1649, 1616, 1561, 1509, 1450, 1419, 1398, 1320, 1288, 1269, 1169, 1124, 1037, 861, 842, 824, 783, 739 cm^–1.

¹H NMR (500.1 MHz, CDCl₃): δ = 1.13 [s, 3 H, C(CH₃)₂], 1.19–1.28 (m, 1 H, CH_2,Cy), 1.37–1.53 (m, 2 H, CH_2,Cy), 1.58–1.60 (m, 1 H, CH_2,Cy), 1.59 [s, 3 H, C(CH₃)₂], 1.73–1.85 (m, 3 H, CH_2,Cy), 1.96–1.99, 2.35–2.41, 3.43–3.49 (3 m, 3 H, CH_2,Cy), 3.49–3.53 (m, 1 H, CH₂C_Ar), 3.78 (s, 3 H, OCH₃), 3.82 (dd, ² J = 20.3 Hz, ⁵ J = 2.3 Hz, 1 H, CH₂C_Ar), 4.90–4.91 (m, 1 H, NCH), 6.61 (d, ⁴ J = 2.5 Hz, 1 H, o-CH _ArCH₂), 6.78 (dd, ³ J = 8.7 Hz, ⁴ J = 2.6 Hz, 1 H, p-CH _ArCH₂), 7.22 (d, ³ J = 8.7 Hz, 1 H, m-CH _ArOCH₃).

¹³C NMR (125.8 MHz, CDCl₃): δ = 24.1, 24.8 (2 × CH_2,Cy), 25.1 [C(CH₃)₂], 26.1 (CH_2,Cy), 26.6 [C(CH₃)₂], 37.5, 38.0 (2 × CH_2,Cy), 39.6 (CH₂C_Ar), 53.0 [C(CH₃)₂], 55.4 (OCH₃), 72.1 (NCH), 76.9 [C(CH_2,Cy)₅], 111.5 (o-CH_ArCH₂), 113.2 (p-CH_ArCH₂), 122.3 (C _ArCH), 127.1 (m-CH_ArOCH₃), 133.6 (C _ArCH₂), 159.1 (C _ArOCH₃), 167.0 (C=O).

MS (CI, isobutane): m/z (%) = 332.2 (100, [MH]⁺).

HRMS (CI, isobutane): m/z calcd for C₁₉H₂₆NO₂S⁺: 332.1684; found: 332.1675.

(RS)-8′-Methoxy-3′,3′-Dimethyl-6′,10b′-dihydro-3′H,5′H-spiro[cyclohexane-1,1′-thiazolo[4,3-a]isoquinolin]-5′-one (4f)

Following GP B, methoxyamide 2f (94 mg, 0.26 mmol) and AlCl₃ (87 mg, 0.65 mmol) were used. Analysis of the crude product by ¹H NMR spectroscopy showed a single regioisomer. The crude product was purified by column chromatography (silica gel; n-hexane–EtOAc­, 4:1); yield: 60 mg (69%); yellow solid; mp 126–127 °C; R_f  = 0.22 (n-hexane–EtOAc, 4:1).

IR (ATR): 3013, 2996, 2971, 2933, 2920, 2859, 2841, 1655, 1613, 1590, 1505, 1464, 1444, 1417, 1290, 1265, 1238, 1227, 1130, 1039, 855, 837, 824 cm^–1.

¹H NMR (500.1 MHz, CDCl₃): δ = 0.93–1.06 (m, 2 H, CH_2,Cy), 1.20–1.29 (m, 1 H, CH_2,Cy), 1.55–1.80 (m, 5 H, CH_2,Cy), 1.76 [s, 3 H, C(CH₃)₂], 1.87–1.93, 1.97–2.00 (2 m, 2 H, CH_2,Cy), 2.07 [s, 3 H, C(CH₃)₂], 3.44–3.48 (m, 1 H, CH₂C_Ar), 3.80 (s, 3 H, OCH₃), 3.80–3.85 (dd, ² J = n.r., ⁵ J = 0.9 Hz, 1 H, CH₂C_Ar), 4.88–4.89 (m, 1 H, NCH), 6.61 (d, ⁴ J = 1.6 Hz, 1 H, o-CH _ArCH₂), 6.80 (dd, ³ J = 8.6 Hz, ⁴ J = 2.3 Hz, 1 H, p-CH _ArCH₂), 7.18 (d, ³ J = 8.6 Hz, 1 H, m-CH _ArOCH₃).

¹³C NMR (125.8 MHz, CDCl₃): δ = 22.2, 25.7, 25.7 (3 × CH_2,Cy), 31.0 [C(CH₃)₂], 31.2 (CH_2,Cy), 32.4 [C(CH₃)₂], 36.8 (CH_2,Cy), 39.3 (CH₂C_Ar), 55.4 (OCH₃), 63.2 [C(CH_2,Cy)₅], 69.5 [C(CH₃)₂], 72.5 (NCH), 111.6 (o-CH_ArCH₂), 113.1 (p-CH_ArCH₂), 121.3 (C _ArCH), 128.2 (m-CH_ArOCH₃), 134.2 (C _ArCH₂), 159.2 (C _ArOCH₃), 166.9 (C=O).

MS (CI, isobutane): m/z (%) = 332.4 (100, [MH]⁺).

HRMS (CI, isobutane): m/z calcd for C₁₉H₂₆NO₂S⁺: 332.1684; found: 332.1676.

(RS)-8′-Methyl-6′,10b′-dihydro-5′H-dispiro[cyclohexane-1,1′-thiazolo[4,3-a]isoquinoline-3′,1′′-cyclohexan]-5′-one (4g)

Following GP B, methoxyamide 2g (101 mg, 0.26 mmol) and AlCl₃ (87 mg, 0.65 mmol) were used. Analysis of the crude product by ¹H NMR spectroscopy showed a single regioisomer. The crude product was purified by column chromatography (silica gel; n-hexane–EtOAc, 4:1); yield: 34 mg (38%); colorless solid; mp 141–142 °C; R_f  = 0.45 (n-hexane–EtOAc, 4:1).

IR (ATR): 2927, 2849, 1656, 1617, 1590, 1509, 1448, 1424, 1402, 1287, 1264, 1246, 1219, 1188, 1172, 1130, 1119, 907, 830, 725 cm^–1.

¹H NMR (500.1 MHz, CDCl₃): δ = 0.92–1.03 (m, 2 H, CH_2,Cy), 1.21–1.42 (m, 2 H, CH_2,Cy), 1.47–2.06 (m, 13 H, CH_2,Cy), 2.13–2.19 (m, 1 H, CH_2,Cy), 2.34 (s, 3 H, CH₃), 3.44–3.48 (m, 1 H, CH₂C_Ar), 3.45–3.51 (m, 1 H, CH_2,Cy), 3.80–3.84 (m, 1 H, CH₂C_Ar), 4.89–4.90 (m, 1 H, NCH), 6.93–6.94 (m, 1 H, o-CH _ArCH₂), 7.04–7.06 (m, 1 H, p-CH _ArCH₂), 7.13 (d, ³ J = 8.0 Hz, 1 H, o-CH _ArCH).

¹³C NMR (125.8 MHz, CDCl₃): δ = 21.2 (CH₃), 22.2, 23.9, 25.0, 25.6, 25.7, 26.2, 31.2, 36.8, 38.2, 38.6 (10xCH_2,Cy), 39.8 (CH₂C_Ar), 61.5 [C(CH_2,Cy)₅CH], 72.7 (NCH), 77.0 [C(CH_2,Cy)₅N], 126.4 (C _ArCH), 127.0 (o-CH_ArCH), 127.1 (p-CH_ArCH₂), 128.0 (o-CH_ArCH₂), 132.6 (C _ArCH₂), 137.8 (C _ArCH₃), 167.3 (C=O).

MS (CI, isobutane): m/z (%) = 356.4 (100, [MH]⁺).

HRMS (CI, isobutane): m/z calcd for C₂₂H₃₀NOS⁺: 356.2048; found: 356.2039.

(RS)-1-(15-Hydroxy-7-thia-14-azadispiro[5.1.5⁸.2⁶]pentadecan-14-yl)-2-(3-methylphenyl)ethan-1-one (5g)

By-product of 4g; yield: 25 mg (27%); colorless, extremely viscous oil; R_f  = 0.30 (n-hexane–EtOAc, 4:1).

IR (ATR): 3379, 2926, 2855, 1628, 1590, 1489, 1448, 1374, 1267, 1252, 1178, 1108, 1072, 1027, 905, 763, 728, 692 cm^–1.

¹H NMR (500.1 MHz, CDCl₃): δ = 1.15–1.38 (m, 6 H, CH_2,Cy), 1.48–1.76 (m, 12 H, CH_2,Cy), 2.32 (s, 3 H, CH₃), 2.87 (d, ³ J = 11.6 Hz, 1 H, OH), 2.98–3.04, 3.06–3.12 (2 m, 2 H, CH_2,Cy), 3.80, 3.85 (2 d, ² J = 15.3 Hz, 2 H, CH₂C_Ar), 5.23 (d, ³ J = 11.6 Hz, 1 H, NCH), 7.03–7.06 (m, 3 H, p-CH _ArCH₂, o-CH _ArCH₂, p-CH _ArCH₃), 7.19–7.22 (m, 1 H, m-CH_Ar).

¹³C NMR (125.8 MHz, CDCl₃): δ = 21.5 (CH₃), 22.2, 24.1, 24.5, 25.3, 25.5, 25.5, 33.6, 36.9, 37.1, 39.7 (10 × CH_2,Cy), 44.8 (CH₂C_Ar), 58.3 [C(CH_2,Cy)₅CH], 78.9 [C(CH_2,Cy)₅N], 90.7 (NCH), 125.8, 127.8 (2 × CH_Ar), 128.7 (m-CH_Ar), 129.5 (CH_Ar), 135.1 (C _ArCH₂), 138.5 (C _ArCH₃), 171.2 (C=O).

MS (CI, isobutane): m/z (%) = 374.5 (100, [MH]⁺), 356.4 (66, [MH – H₂O]⁺).

HRMS (CI, isobutane): m/z calcd for C₂₂H₃₂NO₂S⁺: 374.2154; found: 374.2148.

(RS)-8′-Methoxy-6′,10b′-dihydro-5′H-dispiro[cyclohexane-1,1′-thiazolo[4,3-a]isoquinoline-3′,1′′-cyclohexan]-5′-one (4h)

Following GP B, methoxyamide 2h (81 mg, 0.20 mmol) and AlCl₃ (67 mg, 0.50 mmol) were used. Analysis of the crude product by ¹H NMR spectroscopy showed a single regioisomer. The crude product was purified by column chromatography (silica gel; n-hexane–MTBE­, 7:3); yield: 63 mg (85%); colorless solid; mp 144–146 °C; R_f  = 0.18 (n-hexane–MTBE, 7:3).

IR (ATR): 2928, 2852, 1654, 1613, 1508, 1448, 1410, 1341, 1290, 1265, 1243, 1221, 1169, 1134, 1036, 906, 729 cm^–1.

¹H NMR (500.1 MHz, CDCl₃): δ = 0.92–1.03 (m, 2 H, CH_2,Cy), 1.20–1.41 (m, 2 H, CH_2,Cy), 1.47–1.88 (m, 12 H, CH_2,Cy), 1.94–1.96, 2.02–2.05, 2.13–2.19 (3 m, 3 H, CH_2,Cy), 3.44–3.48 (m, 1 H, CH₂C_Ar), 3.46–3.50 (m, 1 H, CH_2,Cy), 3.80 (s, 3 H, OCH₃), 3.84 (dd, ² J = 19.8 Hz, ⁵ J = 1.0 Hz, 1 H, CH₂C_Ar), 4.86–4.87 (m, 1 H, NCH), 6.62 (d, ⁴ J = 2.3 Hz, 1 H, o-CH _ArCH₂), 6.80 (dd, ³ J = 8.6 Hz, ⁴ J = 2.5 Hz, 1 H, p-CH _ArCH₂), 7.15 (d, ³ J = 8.6 Hz, 1 H, m-CH _ArOCH₃).

¹³C NMR (125.8 MHz, CDCl₃): δ = 22.2, 23.9, 24.9, 25.6, 25.8, 26.1, 31.2, 36.7, 38.2, 38.6 (10 × CH_2,Cy), 40.0 (CH₂C_Ar), 55.4 (OCH₃), 61.5 [C(CH_2,Cy)₅CH], 72.4 (NCH), 76.9 [C(CH_2,Cy)₅N], 111.5 (o-CH_ArCH₂), 113.0 (p-CH_ArCH₂), 121.5 (C _ArCH), 128.3 (m-CH_ArOCH₃), 134.2 (C _ArCH₂), 159.2 (C _ArOCH₃), 167.0 (C=O).

MS (CI, isobutane): m/z (%) = 372.4 (100, [MH]⁺).

HRMS (CI, isobutane): m/z calcd for C₂₂H₃₀NO₂S⁺: 372.1997; found: 372.1999.

(RS)-8-Methoxy-1,1,3,3-tetramethyl-6,10b-dihydro-3H-[1,3]oxazolo[4,3]isoquinolin-5-one (4i)

Following GP B, methoxyamide 2i (111 mg, 0.36 mmol) and AlCl₃ (120 mg, 0.90 mmol) were used. Analysis of the crude product by ¹H NMR spectroscopy showed a single regioisomer. Purification was not necessary; yield: 96 mg (97%); yellow solid; mp 133–134 °C.

IR (ATR): 3077, 2987, 2963, 2938, 2839, 1654, 1612, 1593, 1510, 1463, 1451, 1436, 1401, 1373, 1257, 1245, 1213, 1201, 1169, 1035, 999, 945, 869, 829, 782 cm^–1.

¹H NMR (500.1 MHz, CDCl₃): δ = 1.14, 1.61, 1.67, 1.76 [4 s, 12 H, 2 × C(CH₃)₂], 3.56–3.66 (m, 2 H, CH₂), 3.80 (s, 3 H, OCH₃), 4.62–4.63 (m, 1 H, NCH), 6.69 (d, ⁴ J = 2.0 Hz, 1 H, o-CH _ArCH₂), 6.80 (dd, ³ J = 8.6 Hz, ⁴ J = 2.4 Hz, 1 H, p-CH _ArCH₂), 7.17 (d, ³ J = 8.6 Hz, 1 H, m-CH _ArOCH₃).

¹³C NMR (125.8 MHz, CDCl₃): δ = 23.5, 26.7, 27.5, 28.2 [2 × C(CH₃)₂], 38.8 (CH₂), 55.4 (OCH₃), 65.7 (NCH), 81.0 [C(CH₃)₂CH], 92.7 [C(CH₃)₂N], 112.2 (o-CH_ArCH₂), 113.1 (p-CH_ArCH₂), 122.9 (C _ArCH), 125.4 (m-CH_ArOCH₃), 134.8 (C _ArCH₂), 159.2 (C _ArOCH₃), 165.7 (C=O).

MS (CI, isobutane): m/z (%) = 276.2 (100, [MH]⁺).

HRMS (CI, isobutane): m/z calcd for C₁₆H₂₂NO₃ ⁺: 276.1600; found: 276.1602.

Crystal Data of 4i

Data collection was performed at 153(2) K on a Bruker Kappa Apex II CCD diffractometer, using MoK _α radiation. C₁₆H₂₁NO₃, Mr = 275.34, λ = 0.71073 Ǻ, orthorhombic, space group Pbcn, unit cell dimensions: a = 30.1103(6) Å, b = 8.4760(2) Å, c = 11.3052(2) Å, α = 90°, β = 90°, γ = 90°, V = 2885.26(10) Å³, Z = 8, D _C = 1.268 Mg/m³, absorption coefficient = 0.087 mm^–1, F(000) = 1184, reflections collected 57332, independent reflections 4226 (R_int  = 0.0757). Reflections were collected over the range 3.08° < 2θ < 30.11°, index ranges: –42 < h < 42; –11 < k < 7; –15 < l < 15, completeness to θ = 30.11° is 99.7%. To solve the crystal structure, the SHELXS-97 program was used and for least-squares refinement on F ² the SHELXL-97 program, respectively. Non-hydrogen atoms were refined with anisotropic displacement parameters. All H atoms were placed in calculated positions and refined using a riding model. 4226 reflections were included in calculation, giving final standard residual R ₁ value of 0.0476 (ωR ₂ = 0.1154) for observed data [I > 2σ(I)] and 0.0674 for all data (ωR ₂ = 0.1273) (data/restraints/parameters = 4226:0:186). Largest diff. peak hole 0.374 and –0.242 e/Ǻ³. The goodness-of-fit on F ² was 1.064.

(RS)-9-Methoxy-1,1,3,3-tetramethyl-1,6,7,11b-tetrahydro-3H,5H-benzo[c]thiazolo[3,4-a]azepin-5-one (6a)

Following GP B, methoxyamide 3a (108 mg, 0.32 mmol) and AlCl₃ (107 mg, 0.80 mmol) were used. Analysis of the crude product by ¹H NMR spectroscopy showed a single regioisomer. Purification was not necessary; yield: 92 mg (94%); colorless solid; mp 116–118 °C.

IR (ATR): 3067, 2983, 2967, 2928, 1634, 1610, 1506, 1462, 1446, 1404, 1338, 1291, 1253, 1208, 1190, 1174, 1156, 1112, 1038, 852, 833, 772 cm^–1.

¹H NMR (500.1 MHz, CDCl₃): δ = 1.37, 1.42, 1.72, 1.89 [4 s, 12 H, 2 × C(CH₃)₂], 2.58–3.07 (m, 4 H, 2 × CH₂), 3.78 (s, 3 H, OCH₃), 4.84 (s, 1 H, NCH), 6.68 (d, ⁴ J = 2.4 Hz, 1 H, o-CH _ArCH₂), 6.71 (dd, ³ J = 8.5 Hz, ⁴ J = 2.6 Hz, 1 H, p-CH _ArCH₂), 7.42–7.46 (m, 1 H, m-CH _ArOCH₃).

¹³C NMR (125.8 MHz, CDCl₃): δ = 25.2, 30.1, 30.2, 30.2 [2 × C(CH₃)₂], 30.9 (CH₂C_Ar), 39.0 (CH₂CO), 51.0 [C(CH₃)₂CH], 55.3 (OCH₃), 71.1 [C(CH₃)₂N], 73.8 (NCH), 110.8 (o-CH_ArCH₂), 114.9 (p-CH_ArCH₂), 125.1 (C _ArCH), 130.5 (m-CH_ArOCH₃), 142.5 (C _ArCH₂), 159.1 (C _ArOCH₃), 171.6 (C=O).

MS (CI, isobutane): m/z (%) = 306.3 (100, [MH]⁺).

HRMS (CI, isobutane): m/z calcd for C₁₇H₂₄NO₂S⁺: 306.1528; found: 306.1526.

(RS)-9-Methoxy-1,1,3,3-tetramethyl-1,6,7,11b-tetrahydro-3H,5H-benzo[c]oxazolo[3,4-a]azepin-5-one (6b)

Following GP B, methoxyamide 3b (150 mg, 0.47 mmol) and AlCl₃ (156 mg, 1.17 mmol) were used. Analysis of the crude product by ¹H NMR spectroscopy showed a single regioisomer. The crude product was purified by column chromatography (silica gel; n-hexane–EtOAc, 7:3); yield: 136 mg (~100%); colorless, extremely viscous oil; R_f  = 0.31 (n-hexane–EtOAc, 7:3).

IR (ATR): 2978, 2934, 2862, 2838, 1644, 1612, 1508, 1444, 1414, 1365, 1343, 1278, 1255, 1205, 1171, 1139, 1125, 1103, 1040, 1010, 908, 856, 731 cm^–1.

¹H NMR (500.1 MHz, CDCl₃): δ = 0.91, 1.39, 1.60, 1.73 [4 s, 12 H, 2 × C(CH₃)₂], 2.46–2.51 (m, 1 H, CH₂CO), 2.63–2.68 (m, 1 H, CH₂C_Ar), 2.75–2.80 (m, 1 H, CH₂CO), 3.22–3.27 (m, 1 H, CH₂C_Ar), 3.80 (s, 3 H, OCH₃), 4.66 (s, 1 H, NCH), 6.66 (d, ⁴ J = 2.7 Hz, 1 H, o-CH _ArCH₂), 6.75 (dd, ³ J = 8.6 Hz, ⁴ J = 2.7 Hz, 1 H, p-CH _ArCH₂), 7.13 (d, ³ J = 8.6 Hz, 1 H, m-CH _ArOCH₃).

¹³C NMR (125.8 MHz, CDCl₃): δ = 22.7, 26.2, 26.9, 27.7 [2 × C(CH₃)₂], 31.7 (CH₂C_Ar), 39.5 (CH₂CO), 55.4 (OCH₃), 69.9 (NCH), 82.8 [C(CH₃)₂CH], 93.7 [C(CH₃)₂N], 111.5 (o-CH_ArCH₂), 114.9 (p-CH_ArCH₂), 124.3 (C _ArCH), 130.0 (m-CH_ArOCH₃), 142.9 (C _ArCH₂), 158.6 (C _ArOCH₃), 173.1 (C=O).

MS (CI, isobutane): m/z (%) = 290.2 (100, [MH]⁺).

HRMS (CI, isobutane): m/z calcd for C₁₇H₂₄NO₃ ⁺: 290.1756; found: 290.1759.

Acknowledgment

The silica gel was generously supplied to us by Grace GmbH & Co. KG. T. S. gratefully acknowledges the Heinz-Neumüller-Stiftung for a doctoral fellowship. We thank W. Saak and D. Haase for X-ray crystallography.

• References

• 1 Bieräugel H, Jansen TP, Schoemaker HE, Hiemstra H, van Maarseveen JH. Org. Lett. 2002; 4: 2673
  CrossrefSearch in Google Scholar
• 2 Allen NE, Boyd DB, Campbell JB, Deeter JB, Elzey TK, Foster BJ, Hatfield LD, Hobbs JN. Jr, Hornback WJ, Hunden DC, Jones ND, Kinnick MD, Morin Jr. JM, Munroe JE, Swartzendruber JK, Vogt DG. Tetrahedron 1989; 45: 1905
  CrossrefSearch in Google Scholar
• 3 Delpiccolo CM. L, Mata EG. Tetrahedron: Asymmetry 2002; 13: 905
  CrossrefSearch in Google Scholar
• 4 Lamotte J, Dive G, Ghuysen JM. Eur. J. Med. Chem. 1991; 26: 43
  CrossrefSearch in Google Scholar
• 5 Gunasekera SP, Gunasekera M, McCarthy P. J. Org. Chem. 1991; 56: 4830
  Thieme ConnectSearch in Google Scholar
• 6 Baudoin O, Cesario M, Guénard D, Guéritte F. J. Org. Chem. 2002; 67: 1199
  CrossrefPubMedSearch in Google Scholar
• 7 Christoffers J. Catal. Today 2011; 159: 96
  CrossrefSearch in Google Scholar

For selected examples, see:
• 8a Belaud C, Roussakis C, Letourneux Y, El Alami N, Villieras J. Synth. Commun. 1985; 15: 1233
  CrossrefSearch in Google Scholar
• 8b Annunziata R, Benaglia M, Cinquini M, Cozzi F. Tetrahedron Lett. 1995; 36: 613
  CrossrefSearch in Google Scholar
• 8c Nyzam V, Belaud C, Zammattio F, Villieras J. Tetrahedron: Asymmetry 1996; 7: 1835
  CrossrefSearch in Google Scholar
• 8d Bennett DM, Okamoto I, Danheiser RL. Org. Lett. 1999; 1: 641
  CrossrefSearch in Google Scholar
• 8e Chatani N, Morimoto T, Kamitani A, Fukumoto Y, Murai S. J. Organomet. Chem. 1999; 579: 177
  Search in Google Scholar
• 8f Berger D, Imhof W. Chem. Commun. 1999; 1457
• 8g Yoon CH, Flanigan DL, Chong B.-D, Jung KW. J. Org. Chem. 2002; 67: 6582
  CrossrefSearch in Google Scholar
• 8h Zhang Y.-R, He L, Wu X, Shao P.-L, Ye S. Org. Lett. 2008; 10: 277
  Search in Google Scholar
• 9a Palomo C, Aizpurua JM, Ganboa I, Oiarbide M. Eur. J. Org. Chem. 1999; 3223
• 9b Gómez-Gallego M, Mancheño MJ, Sierra MA. Tetrahedron 2000; 56: 5743
  CrossrefSearch in Google Scholar
• 9c Taggi AE, Hafez AM, Wack H, Young B, Ferraris D, Lectka T. J. Am. Chem. Soc. 2002; 124: 6626
  CrossrefSearch in Google Scholar

For excellent reviews dealing with reactive N-acyliminium ions, see:
• 10a Maryanoff BE, Zhang H.-C, Cohen JH, Turchi IJ, Maryanoff CA. Chem. Rev. 2004; 104: 1431
  CrossrefPubMedSearch in Google Scholar
• 10b Yazici A, Pyne SG. Synthesis 2009; 339
  Thieme Connect
• 10c Martínez-Estibalez U, Gómez-Sanjuan A, García-Calvo O, Aranzamendi E, Lete E, Sotomayor N. Eur. J. Org. Chem. 2011; 3610
• 11a Watzke M, Schulz K, Johannes K, Ullrich P, Martens J. Eur. J. Org. Chem. 2008; 3859
• 11b Schulz K, Watzke M, Johannes K, Ullrich P, Martens J. Synthesis 2009; 665
  Thieme Connect
• 11c Johannes K, Jakob J, Hatam M, Martens J. Synthesis 2009; 3279
  Thieme Connect
• 11d Johannes K, Martens J. Tetrahedron 2010; 66: 242
  CrossrefSearch in Google Scholar
• 11e Johannes K, Watzke M, Martens J. J. Heterocycl. Chem. 2010; 47: 697
  Search in Google Scholar
• 11f Brockmeyer F, Stalling T, Martens J. Synthesis 2012; 44: 2947
  Thieme ConnectSearch in Google Scholar
• 12 Martens J, Janknecht H.-H. Phosphorus, Sulfur Silicon Relat. Elem. 1991; 61: 173
  CrossrefSearch in Google Scholar
• 13 Saari R, Törmä J.-C, Nevalainen T. Bioorg. Med. Chem. 2011; 19: 939
  CrossrefSearch in Google Scholar
• 14 De Luca L, Gitto R, Barreca ML, Caruso R, Quartarone S, Citraro R, De Sarro G, Chimirri A. Arch. Pharm. Chem. Life Sci. 2006; 339: 388
  CrossrefSearch in Google Scholar
• 15a Flemming A. Br. J. Exp. Pathol. 1929; 10: 226
  Search in Google Scholar
• 15b Elander RP. Appl. Microbiol. Biotechnol. 2003; 61: 385
  CrossrefPubMedSearch in Google Scholar
• 15c Gillies PS, Dunn CJ. Drugs 2000; 60: 333
  CrossrefSearch in Google Scholar
• 16 Martens J, Offermanns H, Scherberich P. Angew. Chem., Int. Ed. Engl. 1981; 20: 668 ; Angew. Chem. 1981, 93, 680
  Search in Google Scholar
• 17 Weber M, Jakob J, Martens J. Liebigs Ann. Chem. 1992; 48: 1
  Search in Google Scholar
• 18 CCDC-903533 contains the supplementary crystallographic data for 4i. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
• 19 Fulmer GR, Miller AJ. M, Sherden NH, Gottlieb HE, Nudelman A, Stoltz BM, Bercaw JE, Goldberg KI. Organometallics 2010; 29: 2176
  CrossrefSearch in Google Scholar
• 20 Jetter MC, Youngman MA, McNally JJ, McDonnell ME, Zhang S.-P, Dubin AE, Nasser N, Codd EE, Flores CM, Dax SL. Bioorg. Med. Chem. Lett. 2007; 17: 6160
  CrossrefSearch in Google Scholar
• 21 Katagiri N, Kato T, Nakano J. Chem. Pharm. Bull. 1982; 30: 2440
  CrossrefSearch in Google Scholar
• 22 Pittelkow M, Boas U, Jessing M, Jensen KJ, Christensen JB. Org. Biomol. Chem. 2005; 3: 508
  CrossrefSearch in Google Scholar
• 23 Köpper S, Lindner K, Martens J. Tetrahedron 1992; 48: 10277
  CrossrefSearch in Google Scholar
• 24 Drauz K, Koban HG, Martens J, Schwarze W. Liebigs Ann. Chem. 1985; 448
• 25 Hatam M, Tehranfar D, Martens J. Synth. Commun. 1995; 25: 1677
  CrossrefSearch in Google Scholar
• 26 Gröger H, Martens J. Synth. Commun. 1996; 26: 1903
  CrossrefSearch in Google Scholar

• References

• 1 Bieräugel H, Jansen TP, Schoemaker HE, Hiemstra H, van Maarseveen JH. Org. Lett. 2002; 4: 2673
  CrossrefSearch in Google Scholar
• 2 Allen NE, Boyd DB, Campbell JB, Deeter JB, Elzey TK, Foster BJ, Hatfield LD, Hobbs JN. Jr, Hornback WJ, Hunden DC, Jones ND, Kinnick MD, Morin Jr. JM, Munroe JE, Swartzendruber JK, Vogt DG. Tetrahedron 1989; 45: 1905
  CrossrefSearch in Google Scholar
• 3 Delpiccolo CM. L, Mata EG. Tetrahedron: Asymmetry 2002; 13: 905
  CrossrefSearch in Google Scholar
• 4 Lamotte J, Dive G, Ghuysen JM. Eur. J. Med. Chem. 1991; 26: 43
  CrossrefSearch in Google Scholar
• 5 Gunasekera SP, Gunasekera M, McCarthy P. J. Org. Chem. 1991; 56: 4830
  Thieme ConnectSearch in Google Scholar
• 6 Baudoin O, Cesario M, Guénard D, Guéritte F. J. Org. Chem. 2002; 67: 1199
  CrossrefPubMedSearch in Google Scholar
• 7 Christoffers J. Catal. Today 2011; 159: 96
  CrossrefSearch in Google Scholar

For selected examples, see:
• 8a Belaud C, Roussakis C, Letourneux Y, El Alami N, Villieras J. Synth. Commun. 1985; 15: 1233
  CrossrefSearch in Google Scholar
• 8b Annunziata R, Benaglia M, Cinquini M, Cozzi F. Tetrahedron Lett. 1995; 36: 613
  CrossrefSearch in Google Scholar
• 8c Nyzam V, Belaud C, Zammattio F, Villieras J. Tetrahedron: Asymmetry 1996; 7: 1835
  CrossrefSearch in Google Scholar
• 8d Bennett DM, Okamoto I, Danheiser RL. Org. Lett. 1999; 1: 641
  CrossrefSearch in Google Scholar
• 8e Chatani N, Morimoto T, Kamitani A, Fukumoto Y, Murai S. J. Organomet. Chem. 1999; 579: 177
  Search in Google Scholar
• 8f Berger D, Imhof W. Chem. Commun. 1999; 1457
• 8g Yoon CH, Flanigan DL, Chong B.-D, Jung KW. J. Org. Chem. 2002; 67: 6582
  CrossrefSearch in Google Scholar
• 8h Zhang Y.-R, He L, Wu X, Shao P.-L, Ye S. Org. Lett. 2008; 10: 277
  Search in Google Scholar
• 9a Palomo C, Aizpurua JM, Ganboa I, Oiarbide M. Eur. J. Org. Chem. 1999; 3223
• 9b Gómez-Gallego M, Mancheño MJ, Sierra MA. Tetrahedron 2000; 56: 5743
  CrossrefSearch in Google Scholar
• 9c Taggi AE, Hafez AM, Wack H, Young B, Ferraris D, Lectka T. J. Am. Chem. Soc. 2002; 124: 6626
  CrossrefSearch in Google Scholar

For excellent reviews dealing with reactive N-acyliminium ions, see:
• 10a Maryanoff BE, Zhang H.-C, Cohen JH, Turchi IJ, Maryanoff CA. Chem. Rev. 2004; 104: 1431
  CrossrefPubMedSearch in Google Scholar
• 10b Yazici A, Pyne SG. Synthesis 2009; 339
  Thieme Connect
• 10c Martínez-Estibalez U, Gómez-Sanjuan A, García-Calvo O, Aranzamendi E, Lete E, Sotomayor N. Eur. J. Org. Chem. 2011; 3610
• 11a Watzke M, Schulz K, Johannes K, Ullrich P, Martens J. Eur. J. Org. Chem. 2008; 3859
• 11b Schulz K, Watzke M, Johannes K, Ullrich P, Martens J. Synthesis 2009; 665
  Thieme Connect
• 11c Johannes K, Jakob J, Hatam M, Martens J. Synthesis 2009; 3279
  Thieme Connect
• 11d Johannes K, Martens J. Tetrahedron 2010; 66: 242
  CrossrefSearch in Google Scholar
• 11e Johannes K, Watzke M, Martens J. J. Heterocycl. Chem. 2010; 47: 697
  Search in Google Scholar
• 11f Brockmeyer F, Stalling T, Martens J. Synthesis 2012; 44: 2947
  Thieme ConnectSearch in Google Scholar
• 12 Martens J, Janknecht H.-H. Phosphorus, Sulfur Silicon Relat. Elem. 1991; 61: 173
  CrossrefSearch in Google Scholar
• 13 Saari R, Törmä J.-C, Nevalainen T. Bioorg. Med. Chem. 2011; 19: 939
  CrossrefSearch in Google Scholar
• 14 De Luca L, Gitto R, Barreca ML, Caruso R, Quartarone S, Citraro R, De Sarro G, Chimirri A. Arch. Pharm. Chem. Life Sci. 2006; 339: 388
  CrossrefSearch in Google Scholar
• 15a Flemming A. Br. J. Exp. Pathol. 1929; 10: 226
  Search in Google Scholar
• 15b Elander RP. Appl. Microbiol. Biotechnol. 2003; 61: 385
  CrossrefPubMedSearch in Google Scholar
• 15c Gillies PS, Dunn CJ. Drugs 2000; 60: 333
  CrossrefSearch in Google Scholar
• 16 Martens J, Offermanns H, Scherberich P. Angew. Chem., Int. Ed. Engl. 1981; 20: 668 ; Angew. Chem. 1981, 93, 680
  Search in Google Scholar
• 17 Weber M, Jakob J, Martens J. Liebigs Ann. Chem. 1992; 48: 1
  Search in Google Scholar
• 18 CCDC-903533 contains the supplementary crystallographic data for 4i. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
• 19 Fulmer GR, Miller AJ. M, Sherden NH, Gottlieb HE, Nudelman A, Stoltz BM, Bercaw JE, Goldberg KI. Organometallics 2010; 29: 2176
  CrossrefSearch in Google Scholar
• 20 Jetter MC, Youngman MA, McNally JJ, McDonnell ME, Zhang S.-P, Dubin AE, Nasser N, Codd EE, Flores CM, Dax SL. Bioorg. Med. Chem. Lett. 2007; 17: 6160
  CrossrefSearch in Google Scholar
• 21 Katagiri N, Kato T, Nakano J. Chem. Pharm. Bull. 1982; 30: 2440
  CrossrefSearch in Google Scholar
• 22 Pittelkow M, Boas U, Jessing M, Jensen KJ, Christensen JB. Org. Biomol. Chem. 2005; 3: 508
  CrossrefSearch in Google Scholar
• 23 Köpper S, Lindner K, Martens J. Tetrahedron 1992; 48: 10277
  CrossrefSearch in Google Scholar
• 24 Drauz K, Koban HG, Martens J, Schwarze W. Liebigs Ann. Chem. 1985; 448
• 25 Hatam M, Tehranfar D, Martens J. Synth. Commun. 1995; 25: 1677
  CrossrefSearch in Google Scholar
• 26 Gröger H, Martens J. Synth. Commun. 1996; 26: 1903
  CrossrefSearch in Google Scholar