Subscribe to RSS
DOI: 10.1055/s-0028-1083342
Synthesis of Bi- and Tricyclic α,β-Unsaturated Lactams as Potential Michael Acceptors Starting from Heterocyclic Imines
Publication History
Publication Date:
27 January 2009 (online)
Abstract
New α,β-unsaturated valerolactams showing potential as Michael acceptors were synthesized from heterocyclic imines as starting materials. The synthetic procedure is based on an acid chloride addition in the first step, followed by a modified Hosomi-Sakurai reaction, and a final ring-closing metathesis using a ruthenium catalyst.
Key words
heterocycles - imines - unsaturated lactams - Michael acceptor - ring-closing metathesis
α,β-Unsaturated valerolactams are interesting substances on the one hand because of their character as Michael acceptors and on the other because of their high bioactivity. Unsaturated valerolactams were previously reported, for example, as antivirals, cytotoxic, and antifungal compounds. [¹] Different ways of synthesizing unsaturated valerolactams were described in literature. [²]
Furthermore, the heterocyclic amine core of the resulting lactams represents an interesting building block for several bioactive compounds. 3-Thiazolidine derivatives, for example, are substructures of penicillins [³] and diabetes mellitus drugs. [4] Clavulanic acid, which is a strong β-lactamase inhibitor contains a 3-oxazolidine structure, [³d] [5] and the benzo[1,4]thiazine and the benzo[1,4]oxazine substructures are potent potassium and calcium channel openers, [6] inflammatory inhibitors [7] or antibiotica. [8]
Starting from heterocyclic imine precursors prepared via α-halogen aldehydes, our aim was to synthesize α,β-unsaturated valerolactams, beginning with an acid chloride addition followed by a modified Hosomi-Sakurai reaction and including a ring-closing metathesis as a final step. This synthesis sequence offers access to a great number of new Michael acceptors and potentially bioactive lactams starting from heterocyclic imines.
We focused our attention on different heterocyclic imines serving as precursors in the multilevel synthesis of lactams. The monocyclic five-membered 2,5-dihydrothiazole 1a [9] and 2,5-dihydrooxazole 1b [¹0] were synthesized by a modified Asinger protocol starting from 2-chloro-2-methylpropanal. The bicyclic 2H-benzo[1,4]thiazine 2a [¹¹] and the 2H-benzo[1,4]oxazine 2b [¹² ] were prepared of 2-bromo-2-methylpropanal and 2-aminothiophenol or 2-aminophenol (Scheme [¹] ).
Scheme 1 Precursors used for the synthesis of 1
In the first step of the synthesis, an addition of acid chlorides to the heterocyclic imines was employed. This type of reaction goes back to Böhme and Hartke, [¹³] who added acid chlorides to linear imines to produce sensitive α-chloro amides. In the presence of tertiary amines, a substitution of chloride for hydroxy or alkoxy group follows. Schwarze et al. [¹4] extended this reaction to cyclic imines. Thus, we chose acryloyl and methacryloyl chloride for addition to the heterocyclic imines 1 and 2 (Scheme [²] ). Without isolation of the chloro compounds, methanol in the presence of triethylamine was added to afford α-methoxy acrylamides 3 and 4 in good yields up to 86% (Table [¹] ).
The Hosomi-Sakurai reaction was used to transfer allyl moiety to carbonyl compounds so that unsaturated alcohols were obtained. [¹5] As reported in literature, [¹6] this type of reaction was transferred to acyl iminium ions successfully. The alkoxy amide is activated by a Lewis acid so that an acyl iminium ion is formed. The alkylation reagent attacks the formed ion in nucleophilic way. Thus, we treated the α-methoxy acrylamides 3,4 with allyltrimethylsilane in the presence of titanium(IV) chloride (Scheme [²] ). The obtained α-allyl acrylamides 5,6 are used for ring-closing metathesis (Table [¹] ).
The ring-closing metathesis was the final step in the synthesis of the desired α,β-unsaturated δ-lactams. The use of acrylamides as substrates for the ring-closing metathesis has been reported for a few examples. [¹7] The ruthenium catalyst I, a catalyst comparable to the Grubbs II catalysts, was chosen for our synthesis (Figure [¹] ). [¹8]
The cyclizations were performed in toluene using 5 mol% of catalyst I, starting at room temperature and a slow increase of temperature up to 70 ˚C (Scheme [²] ). The reactions were controlled by TLC and stopped when no α-allyl acrylamide 5,6 was detected in the reaction mixture anymore. The lactams 7 and 8 were obtained in good yields - up to 88% (Table [¹] ). We were able to obtain single crystals of compound 8a and determined the proposed structure by an X-ray crystal structure analysis (Figure [²] ). [¹] [9]
Scheme 2 Synthesis of lactams 7 and 8. Reagents and conditions: (a) (i) CH2C(R)COCl, CH2Cl2, 0-5 ˚C, (ii) r.t., 3 h; (b) (i) MeOH, Et3N, CH2Cl2, 0-5 ˚C, (ii) r.t., 1 h, 42-86%; (c) CH2=CHCH2SiMe3, TiCl4, CH2Cl2, -30 ˚C, 1.5 h, (ii) r.t., 18 h, 17-96%; (d) catalyst I, toluene, up to 70 ˚C, 56-88%.
Figure 1 Used ruthenium catalyst I
Figure 2 ORTEP representation of lactam 8a in the solid state
In order to show the potential as Michael acceptor, an exploratory experiment was made. The synthesized α,β-unsaturated lactam 7a was functionalized with thioacetic acid to ester 9 in 90% yield resulting in a single diastereomer as product (Scheme [³] ).
Scheme 3 Addition of thioacetic acid on Michael acceptor 7a. Reagents and conditions: (a) CH3COSH, AIBN, 100 ˚C, 6 h, 90%.
This successful addition exemplifies the possibility for other modifications. Experiments for further derivatizations of Michael acceptors 7,8 are still in progress.
In conclusion, we have synthesized the new α,β-unsaturated valerolactams 7,8 starting from heterocyclic imines 1,2 via an acid chloride addition followed by a modified Hosomi-Sakurai reaction and finally by a ring-closing metathesis. As shown in an exploratory experiment, functionalizations of lactams 7,8 are possible. Thus, this synthesis sequence offers access to new Michael acceptors.
Synthetic procedures were performed on a vacuum line using standard Schlenk techniques under argon. All reagents and solvents were commercial grade and purified prior to use when necessary. 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. ¹H and ¹³C NMR spectra were recorded with Bruker Avance DRX 500 and Avance DPX 300 spectrometers. NMR chemical shifts are reported in ppm. Assignments of the signals in the ¹³C NMR spectrum were supported by measurements applying DEPT and COSY techniques. EI-MS, CI-MS, and HRMS spectra were recorded on a Finnigan MAT 95 spectrometer. IR spectra were recorded on a Bruker Tensor 27 spectrometer equipped with a GoldenGate diamond-ATR unit.
α-Methoxy Acrylamides 3 and 4; General Procedure (GP A)
Under argon, the respective imine 1, 2 (1 equiv) was dissolved in anhyd CH2Cl2 (10 mL) and cooled to 0-5 ˚C before the acid chloride (1.1 equiv) was added dropwise. After stirring for 3 h at r.t., a mixture of MeOH (3.7 equiv) and anhyd Et3N (1.75 equiv) in anhyd CH2Cl2 (10 mL) was added dropwise at 0-5 ˚C. After stirring for 1 h at r.t., the solution was poured into ice-water (20 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (3 × 20 mL). The combined organic phases were washed with sat. aq NaHCO3 (20 mL), H2O (2 × 20 mL), and dried (MgSO4). The solvent was removed under reduced pressure and the product was purified as described below.
1-(4-Methoxy-2,2,5,5-tetramethylthiazolidin-3-yl)propenone (3a)
Following GP A, dihydrothiazole 1a (3.50 g, 24.4 mmol), acryloyl chloride (2.21 g, 24.4 mmol), anhyd MeOH (2.94 g, 91.6 mmol), and Et3N (4.32 g, 42.8 mmol) were used. The crude product was crystallized from CH2Cl2 and n-hexane at -30 ˚C; yield: 3.80 g (16.6 mmol, 68%); colorless solid; mp 46 ˚C.
IR: 2965, 2931, 2828, 1652, 1613, 1468, 1408, 1359, 1343, 1081, 995 cm-¹.
¹H NMR (500 MHz, CDCl3): δ = 1.34 [s, 3 H, SC(CH 3)2CH], 1.45 [s, 3 H, SC(CH 3)2CH], 1.79 [s, 3 H, SC(CH 3)2N], 1.90 [s, 3 H, SC(CH 3)2N], 3.30 (s, 3 H, OCH3), 4.96 (br s, 1 H, NCH), 5.67 (d, ³ J = 10.4 Hz, 1 H, COCH=CH 2), 6.28 (d, ³ J = 16.6 Hz, 1 H, COCH=CH 2), 6.53 (dd, ³ J = 10.4 Hz, ³ J = 16.6 Hz, 1 H, COCH=CH2).
¹³C NMR (126 MHz, CDCl3): δ = 23.0 [SC(CH3)2CH], 30.9 [SC(CH3)2N], 52.4 [SC(CH3)2CH], 55.2 (OCH3), 72.3 [SC(CH3)2N], 98.9 (NCH), 128.2 (COCH=CH2), 130.3 (COCH=CH2), 165.7 (C=O).
MS (CI, isobutane): m/z (%) = 230.3 (100, [M + H]+).
HRMS (CI, isobutane): m/z calcd for [C11H20NO2S]+: 230.1215; found: 230.1216.
1-(4-Methoxy-2,2,5,5-tetramethylthiazolidin-3-yl)-2-methylpropenone (3b)
Following GP A, dihydrothiazole 1a (0.40 g, 2.8 mmol), methacryloyl chloride (0.32 g, 2.8 mmol), anhyd MeOH (0.34 g, 10.5 mmol), and Et3N (0.49 g, 4.9 mmol) were used. The crude product was purified by column chromatography (silica gel; n-hexane-EtOAc, 7:3); yield: 0.59 g (2.4 mmol, 86%); colorless oil; R f = 0.53 (n-hexane-EtOAc, 7:3).
IR: 3087, 2979, 2932, 2864, 2828, 1650, 1628, 1466, 1450, 1386, 1356, 1079, 860 cm-¹.
¹H NMR (500 MHz, CDCl3): δ = 1.37 [s, 3 H, SC(CH 3)2CH], 1.54 [s, 3 H, SC(CH 3)2CH], 1.85 [s, 3 H, SC(CH 3)2N], 1.92 [s, 3 H, SC(CH 3)2N], 2.00 [dd, 4 J = 1.1 Hz, 4 J = 1.6 Hz, 3 H, COC(CH 3)=CH2], 3.31 (s, 3 H, OCH3), 5.16 (s, 1 H, NCH), 5.16 [s, 1 H, COC(CH3)=CH 2], 5.30 [qd, ² J = 3.3 Hz, 4 J = 1.6 Hz, 1 H, COC(CH3)=CH 2].
¹³C NMR (126 MHz, CDCl3): δ = 20.5 [COC(CH3)=CH2], 23.1 [SC(CH3)2CH], 31.0, 31.4, 31.4 [SC(CH3)2CH, SC(CH3)2N], 52.7 [SC(CH3)2CH], 55.6 (OCH3), 71.9 [SC(CH3)2N], 100.7 (NCH), 117.6 [COC(CH3)=CH2], 142.1 [COC(CH3)=CH2], 171.5 (C=O).
MS (CI, isobutane): m/z (%) = 244.0 (21, [M + H]+), 212.0 (31, [M - OCH3]+), 126.0 (100, [C7H12NO]+).
HRMS (CI, isobutane): m/z calcd for [C12H22NO2S]+: 244.1371; found: 244.1372.
1-(4-Methoxy-2,2,5,5-tetramethyloxazolidin-3-yl)propenone (3c)
Following GP A, dihydrooxazole 1b (0.64 g, 5.0 mmol), acryloyl chloride (0.50 g, 5.5 mmol), anhyd MeOH (0.59 g, 18.5 mmol), and Et3N (0.89 g, 8.8 mmol) were used. The crude product was purified by column chromatography (silica gel; n-hexane-EtOAc, 1:1); yield: 0.45 g (2.1 mmol, 42%); yellow oil; R f = 0.64 (n-hexane-EtOAc, 1:1).
IR: 2985, 2940, 1661, 1618, 1418, 1084 cm-¹.
¹H NMR (500 MHz, CDCl3): δ = 1.30 [s, 3 H, OC(CH 3)2CH], 1.35 [s, 3 H, OC(CH 3)2CH], 1.60 [s, 3 H, OC(CH 3)2N], 1.67 [s, 3 H, OC(CH 3)2N], 3.37 (s, 3 H, OCH3), 4.78 (br s, 1 H, NCH), 5.73 (dd, ² J = 2.0 Hz, ³ J = 9.9 Hz, 1 H, COCH=CH 2), 6.41 (dd, ² J = 2.0 Hz, ³ J = 16.6 Hz, 1 H, COCH=CH 2), 6.49 (dd, ³ J = 9.9 Hz, ³ J = 16.6 Hz, 1 H, COCH=CH2).
¹³C NMR (126 MHz, CDCl3): δ = 22.8 [OC(CH3)2CH], 27.6 [OC(CH3)2N], 27.7 [OC(CH3)2CH], 27.8 [OC(CH3)2N], 56.1 (OCH3), 81.7 [OC(CH3)2CH], 93.3 (NCH), 95.5 [OC(CH3)2N], 128.5 (COCH=CH2), 129.1 (COCH=CH2), 164.2 (C=O).
MS (CI, isobutane): m/z (%) = 214.1 (100, [M + H]+), 182.1 (33, [M - OCH3]+).
HRMS (CI, isobutane): m/z calcd for [C11H20NO3]+: 214.1443; found: 214.1443.
1-(4-Methoxy-2,2,5,5-tetramethyloxazolidin-3-yl)-2-methylpropenone (3d)
Following GP A, dihydrooxazole 1b (0.64 g, 5.0 mmol), methacryloyl chloride (0.57 g, 5.5 mmol), anhyd MeOH (0.59 g, 18.5 mmol), and Et3N (0.89 g, 8.8 mmol) were used. The crude product was purified by column chromatography (silica gel; n-hexane-EtOAc, 7:3); yield: 0.53 g (2.3 mmol, 47%); yellow oil; R f = 0.56 (n-hexane-EtOAc, 7:3).
IR: 2982, 2938, 1656, 1628, 1453, 1364, 1079 cm-¹.
¹H NMR (500 MHz, CDCl3): δ = 1.32 [s, 3 H, OC(CH 3)2CH], 1.33 [s, 3 H, OC(CH 3)2CH], 1.60 [s, 3 H, OC(CH 3)2N], 1.64 [s, 3 H, OC(CH 3)2N], 2.00 [s, 3 H, COC(CH 3)=CH2], 3.29 (s, 3 H, OCH3), 4.90 (br s, 1 H, NCH), 5.15 [s, 1 H, COC(CH3)=CH 2], 5.28 [s, 1 H, COC(CH3)=CH 2].
¹³C NMR (126 MHz, CDCl3): δ = 20.3 [COC(CH3)=CH2], 22.6 [OC(CH3)2CH], 27.5 [OC(CH3)2N, OC(CH3)2CH], 28.0 [OC(CH3)2N], 56.4 (OCH3), 81.4 [OC(CH3)2CH], 95.0 [NCH, OC(CH3)2N], 116.3 [COC(CH3)=CH2], 141.8 [COC(CH3)=CH2], 170.8 (C=O).
MS (CI, isobutane): m/z (%) = 228.3 (100, [M + H]+), 196.3 (19, [M - OCH3]+).
HRMS (CI, isobutane): m/z calcd for [C12H22NO3]+: 228.1600; found: 228.1599.
1-(3-Methoxy-2,2-dimethyl-2,3-dihydrobenzo[1,4]thiazin-4-yl)propenone (4a)
Following GP A, benzothiazine 2a (0.50 g, 2.8 mmol), acryloyl chloride (0.28 g, 3.1 mmol), anhyd MeOH (0.33 g, 10.4 mmol), and Et3N (0.50 g, 4.9 mmol) were used. The crude product was purified by column chromatography (silica gel; n-hexane-EtOAc, 7:3); yield: 0.38 g (1.4 mmol, 51%); colorless solid; mp 111 ˚C; R f = 0.50 (n-hexane-EtOAc, 7:3).
IR: 3057, 2967, 2927, 1657, 1463, 1260, 738 cm - ¹.
¹H NMR (500 MHz, CDCl3): δ = 1.37 (s, 3 H, CH3), 1.47 (s, 3 H, CH3), 3.32 (s, 3 H, OCH3), 5.76 (dd, ² J = 2.8 Hz, ³ J = 9.2 Hz, 1 H, COCH=CH2), 5.81 (s, 1 H, NCH), 6.43-6.54 (m, 2 H, COCH=CH 2), 7.06 (dd, ³ J = 7.7 Hz, 4 J = 1.9 Hz, 1 H, o-CHArN), 6.96-7.11 (m, 3 H, HAr).
¹³C NMR (126 MHz, CDCl3): δ = 25.8 (CH3), 30.4 (CH3), 47.6 [C(CH3)2], 55.9 (OCH3), 84.6 (NCH), 123.7, 125.7, 126.2, 126.6 (CHAr), 128.6 (CArS), 129.4 (COCH=CH2), 130.5 (CArN), 133.4 (COCH=CH2), 166.4 (C=O).
MS (CI, isobutane): m/z (%) = 264.1 (10, [M + H]+), 232.0 (100, [M - OCH3]+).
HRMS (EI): m/z calcd for C14H17NO2S: 263.0980; found: 263.0981.
1-(3-Methoxy-2,2-dimethyl-2,3-dihydrobenzo[1,4]thiazin-4-yl)-2-methylpropenone (4b)
Following GP A, benzothiazine 2a (0.50 g, 2.8 mmol), methacryloyl chloride (0.32 g, 3.1 mmol), anhyd MeOH (0.33 g, 10.4 mmol), and Et3N (0.50 g, 4.9 mmol) were used. The crude product was purified by column chromatography (silica gel; n-hexane-EtOAc, 7:3); yield: 0.33 g (1.2 mmol, 42%); colorless solid; mp 102 ˚C; R f = 0.58 (n-hexane-EtOAc, 7:3).
IR: 3054, 2977, 2939, 1646, 1477, 1197, 729 cm - ¹.
¹H NMR (500 MHz, CDCl3): δ = 1.45 (s, 3 H, CH3), 1.47 (s, 3 H, CH3), 1.85 [s, 3 H, COC(CH 3)=CH2], 3.30 (s, 3 H, OCH3), 5.22-5.28 [m, 2 H, CO(CH3)=CH 2], 5.73 (s, 1 H, NCH), 6.89-6.96 (m, 2 H, CHAr), 7.00 (ddd, ³ J = 7.3 Hz, ³ J = 7.9 Hz, 4 J = 2.0 Hz, 1 H, p-CHArN), 7.07 (dd, ³ J = 7.9 Hz, 4 J = 0.7 Hz, 1 H, o-CHArS).
¹³C NMR (126 MHz, CDCl3): δ = 19.5 [COC(CH3)=CH2], 26.3 (CH3), 30.9 (CH3), 48.5 [C(CH3)2], 55.8 (OCH3), 84.6 (NCH), 121.9 [COC(CH3)=CH2], 123.6, 125.4, 125.7, 125.9 (CHAr), 128.0 (CArS), 132.0 (CArN), 140.3 [COC(CH3)=CH2], 171.6 (C=O).
MS (CI, isobutane): m/z (%) = 277.1 (25, [M + H]+), 246.0 (100, [M - OCH3]+).
HRMS (EI): m/z calcd for C15H19NO2S: 277.1137; found: 277.1137.
1-(3-Methoxy-2,2-dimethyl-2,3-dihydrobenzo[1,4]oxazin-4-yl)propenone (4c)
Following GP A, benzoxazine 2b (96 mg, 0.60 mmol), acryloyl chloride (59 mg, 0.66 mmol), anhyd MeOH (71 mg, 2.21 mmol), and Et3N (105 mg, 1.04 mmol) were used. The crude product was purified by column chromatography (silica gel; n-hexane-EtOAc, 8:3); yield: 79 mg (0.32 mmol, 56%); colorless solid; mp 85-89 ˚C; R f = 0.55 (n-hexane-EtOAc, 8:3).
IR: 3061, 2980, 2931, 1657, 1497, 1262, 749 cm - ¹.
¹H NMR (500 MHz, CDCl3): δ = 1.19 (s, 3 H, CH3), 1.51 (s, 3 H, CH3), 3.36 (s, 3 H, OCH3), 5.51-5.63 (m, 1 H, NCH), 5.85 (dd, ² J = 1.7 Hz, ³ J = 10.1 Hz, 1 H, COCH=CH 2), 6.57 (dd, ² J = 1.7 Hz, ³ J = 16.9 Hz, 1 H, COCH=CH 2), 6.72 (dd, ³ J = 10.2 Hz, ³ J = 16.9 Hz, 1 H, COCH=CH2), 6.88 (ddd, ³ J = 7.3 Hz, ³ J = 7.3 Hz, 4 J = 1.2 Hz, 1 H, p-CHArO), 6.91 (dd, ³ J = 8.5 Hz, 4 J = 1.1 Hz, 1 H, o-CHArO), 7.03-7.08 (m, 1 H, o-CHArN), 7.09-7.12 (m, 1 H, p-CHArN).
¹³C NMR (126 MHz, CDCl3): δ = 24.0 (CH3), 24.4 (CH3), 55.6 (OCH3), 82.4 [C(CH3)2], 82.4 (NCH), 117.5 (o-CHArO), 119.9 (p-CHArO), 121.0 (CArN), 124.4 (o-CHArN), 126.4 (p-CHArN), 129.0 (COCH=CH2), 129.9 (COCH=CH2), 146.0 (CArO), 165.5 (C=O).
MS (CI, isobutane): m/z (%) = 247.1 (100, [M + H]+).
HRMS (CI, isobutane): m/z calcd for [C14H18NO3]+: 247.1208; found: 247.1208.
1-(3-Methoxy-2,2-dimethyl-2,3-dihydrobenzo[1,4]oxazin-4-yl)-2-methylpropenone (4d)
Following GP A, benzoxazine 2b (95 mg, 0.59 mmol), methacryloyl chloride (68 mg, 0.65 mmol), anhyd MeOH (71 mg, 2.21 mmol), and Et3N (105 mg, 1.04 mmol) were used. The crude product was purified by column chromatography (silica gel; n-hexane-EtOAc, 7:3); yield: 127 mg (0.49 mmol, 82%); colorless solid; mp 90-95 ˚C; R f = 0.53 (n-hexane-EtOAc, 7:3).
IR: 3061, 2933, 1650, 1494, 1092, 738 cm - ¹.
¹H NMR (500 MHz, CDCl3): δ = 1.27 (s, 3 H, CH3), 1.50 (s, 3 H, CH3), 1.97 [s, 3 H, COC(CH 3)=CH2], 3.35 (s, 3 H, OCH3), 5.34 [d, ² J = 1.6 Hz, 1 H, COC(CH3)=CH 2], 5.38 [d, ² J = 1.6 Hz, 1 H, COC(CH3)=CH 2], 5.48 (s, 1 H, NCH), 6.78-6.82 (m, 1 H, p-CHArO), 6.88 (dd, ³ J = 8.2 Hz, 4 J = 1.4 Hz, 1 H, o-CHArO), 7.02-7.06 (m, 1 H, p-CHArN), 7.15-7.19 (m, 1 H, o-CHArN).
¹³C NMR (126 MHz, CDCl3): δ = 19.9 [COC(CH3)=CH2], 24.4 (CH3), 24.9 (CH3), 55.7 (OCH3), 77.3 [C(CH3)2], 82.2 (NCH), 117.3 (o-CHArO), 119.7 (p-CHArO), 120.9 [COC(CH3)=CH2], 121.7 (CArN), 123.5 (o-CHArN), 126.0 (p-CHArN), 140.5 [COC(CH3)=CH2], 145.3 (CArO), 170.4 (C=O).
MS (CI, isobutane): m/z (%) = 261.1 (100, [M + H]+).
HRMS (CI, isobutane): m/z calcd for [C15H19NO3]+: 261.1365; found: 261.1365.
α-Allyl Acrylamides 5 and 6; General Procedure (GP B)
Under argon, the respective α-methoxy acrylamide 3, 4 (1 equiv) synthesized according to GP A was dissolved in anhyd CH2Cl2 (20 mL) and cooled to -30 ˚C before allyltrimethylsilane (1.5 equiv) dissolved in anhyd CH2Cl2 (10 mL) was added dropwise. Then, TiCl4 (2 equiv) dissolved in anhyd CH2Cl2 (10 mL) was added dropwise. After stirring for 1.5 h at -30 ˚C and 18 h at r.t., the solution was poured into ice-water (30 mL). The phases were separated and the organic phase was washed with H2O (2 × 20 mL) and dried (MgSO4). The solvent was removed under reduced pressure and the product was purified as described below.
1-(4-Allyl-2,2,5,5-tetramethylthiazolidin-3-yl)propenone (5a)
Following GP B, α-methoxy acrylamide 3a (4.20 g, 18.3 mmol), allyltrimethylsilane (3.14 g, 27.5 mmol), and TiCl4 (6.95 g, 36.6 mmol) were used. The product was obtained as a colorless oil and used without further purification; yield: 4.20 g (17.6 mmol, 96%).
IR: 3083, 2983, 2935, 1647, 1615, 1411, 1361, 976, 918 cm-¹.
¹H NMR (500 MHz, CDCl3): δ = 1.28 [s, 3 H, SC(CH 3)2CH], 1.54 [s, 3 H, SC(CH 3)2CH], 1.79 [s, 3 H, SC(CH 3)2N], 1.95 [s, 3 H, SC(CH 3)2N], 2.45-2.51 (m, 1 H, CH 2CH=CH2), 2.63-2.68 (m, 1 H, CH 2CH=CH2), 4.05 (br s, 1 H, NCH), 5.03 (d, ³ J = 10.2 Hz, 1 H, CH2CH=CH 2), 5.09 (d, ³ J = 17.0 Hz, 1 H, CH2CH=CH 2), 5.57 (dd, ² J = 1.1 Hz, ³ J = 10.4 Hz, 1 H, COCH=CH 2), 5.69-5.77 (m, 1 H, CH2CH=CH2), 6.22 (dd, ² J = 1.1 Hz, ³ J = 16.6 Hz, 1 H, COCH=CH 2), 6.44 (dd, ³ J = 10.4 Hz, ³ J = 16.6 Hz, 1 H, COCH=CH2).
¹³C NMR (126 MHz, CDCl3): δ = 23.9 [SC(CH3)2CH], 30.3 [SC(CH3)2N], 32.6 [SC(CH3)2CH], 38.2 (CH2CH=CH2), 39.9 [SC(CH3)2CH], 52.0 [SC(CH3)2N], 72.1 (NCH), 118.4 (CH2CH=CH2), 127.1 (COCH=CH2), 131.0 (COCH=CH2), 134.5 (CH2 CH=CH2), 164.9 (C=O).
MS (CI, isobutane): m/z (%) = 479.3 (19, [M2H]+), 240.1 (100, [M + H]+), 198.1 (19, [MH - C3H5]+).
HRMS (CI, isobutane): m/z calcd for [C13H22NOS]+: 240.1422; found: 240.1423.
1-(4-Allyl-2,2,5,5-tetramethylthiazolidin-3-yl)-2-methylpropenone (5b)
Following GP B, α-methoxy acrylamide 3b (0.25 g, 1.1 mmol), allyltrimethylsilane (0.19 g, 1.6 mmol), and TiCl4 (0.41 g, 2.2 mmol) were used. The crude product was purified by column chromatography (silica gel; n-hexane-EtOAc, 7:3); yield: 115 mg (0.45 mmol, 42%); colorless oil; R f = 0.65 (n-hexane-EtOAc, 7:3).
IR: 3079, 2979, 2932, 1641, 1620, 1450, 1408, 1374, 1362, 913 cm-¹.
¹H NMR (300 MHz, CDCl3): δ = 1.28 [s, 3 H, SC(CH 3)2CH], 1.61 [s, 3 H, SC(CH 3)2CH], 1.82 [s, 3 H, SC(CH 3)2N], 1.94 [s, 3 H, SC(CH 3)2N], 1.94 [s, 3 H, COC(CH 3)=CH2], 2.48 (ddd, ² J = 14.1 Hz, ³ J = 6.8 Hz, ³ J = 7.0 Hz, 1 H, CH 2CH=CH2), 2.68 (ddd, ² J = 14.1 Hz, ³ J = 6.8 Hz, ³ J = 6.8 Hz, 1 H, CH 2CH=CH2), 4.23 (dd, ³ J = 6.8 Hz, ³ J = 6.8 Hz, 1 H, NCH), 5.08-5.14 [m, 4 H, COC(CH3)=CH 2, CH2CH=CH 2], 5.64-5.77 (m, 1 H, CH2CH=CH2).
¹³C NMR (126 MHz, CDCl3): δ = 20.7 [COC(CH3)=CH2], 24.0 [SC(CH3)2CH], 30.6 [SC(CH3)2CH], 32.0 [SC(CH3)2N], 32.9 [SC(CH3)2N], 38.5 (CH2CH=CH2), 52.4 [SC(CH3)2CH], 71.5 (NCH), 73.1 [SC(CH3)2N], 115.6 (CH2CH=CH2), 118.2 [COC(CH3)=CH2], 135.1 (CH2 CH=CH2), 143.0 [COC(CH3)=CH2], 171.0 (C=O).
MS (CI, isobutane): m/z (%) = 254.2 (100, [M + H]+).
HRMS (CI, isobutane): m/z calcd for [C14H24NOS]+: 254.1579; found: 254.1580.
1-(4-Allyl-2,2,5,5-tetramethyloxazolidin-3-yl)propenone (5c)
Following GP B, α-methoxy acrylamide 3c (0.42 g, 2.0 mmol), allyltrimethylsilane (0.34 g, 3.0 mmol), and TiCl4 (0.75 g, 3.9 mmol) were used. The crude product was purified by column chromatography (silica gel; n-hexane-EtOAc, 7:3); yield: 0.30 g (1.3 mmol, 67%); light yellow oil; R f = 0.64 (n-hexane-EtOAc, 7:3).
IR: 3076, 2981, 2938, 1648, 1613, 1417, 1367, 1000, 915 cm-¹.
¹H NMR (500 MHz, CDCl3): δ = 1.29 [s, 3 H, OC(CH 3)2CH], 1.33 [s, 3 H, OC(CH 3)2CH], 1.58 [s, 3 H, OC(CH 3)2N], 1.70 [s, 3 H, OC(CH 3)2N], 2.24-2.29 (m, 1 H, CH 2CH=CH2), 2.50-2.57 (m, 1 H, CH 2CH=CH2), 3.76-3.85 (m, 1 H, NCH), 5.06-5.11 (m, 2 H, CH2CH=CH 2), 5.65 (d, ³ J = 9.7 Hz, 1 H, COCH=CH 2), 5.71-5.79 (m, 1 H, CH2CH=CH2), 6.35 (d, ³ J = 16.4 Hz, 1 H, COCH=CH 2), 6.42 (dd, ³ J = 9.7 Hz, ³ J = 16.4 Hz, 1 H, COCH=CH2).
¹³C NMR (126 MHz, CDCl3): δ = 23.8 [OC(CH3)2CH], 27.7 [OC(CH3)2N], 28.3 [OC(CH3)2N], 29.4 [OC(CH3)2CH], 37.5 (CH2CH=CH2), 64.9 (NCH), 80.3 [OC(CH3)2CH], 94.3 [OC(CH3)2N], 118.3 (CH2CH=CH2), 127.7 (COCH=CH2), 129.6 (COCH=CH2), 134.4 (CH2 CH=CH2), 163.0 (C=O).
MS (CI, isobutane): m/z (%) = 224.1 (100, [M + H]+).
HRMS (CI, isobutane): m/z calcd for [C13H22NO2]+: 224.1651; found: 224.1650.
1-(4-Allyl-2,2,5,5-tetramethyloxazolidin-3-yl)-2-methylpropenone (5d)
Following GP B, α-methoxy acrylamide 3d (0.51 g, 2.24 mmol), allyltrimethylsilane (0.38 g, 3.4 mmol), and TiCl4 (0.85 g, 4.5 mmol) were used. The crude product was purified by column chromatography (silica gel; n-hexane-EtOAc, 2:1); yield: 0.13 g (0.6 mmol, 25%); colorless solid; mp 40-41 ˚C; R f = 0.58 (n-hexane-EtOAc, 2:1).
IR: 3076, 2981, 2942, 1642, 1608, 1419, 1401, 1365, 998, 912 cm-¹.
¹H NMR (500 MHz, CDCl3): δ = 1.29 [s, 3 H, COC(CH 3)2CH], 1.39 [s, 3 H, COC(CH 3)2CH], 1.62 [s, 3 H, COC(CH 3)2N], 1.68 [s, 3 H, COC(CH 3)2N], 1.99 [br s, 3 H, COC(CH 3)=CH2], 2.22-2.28 (m, 1 H, CH 2CH=CH2), 2.46-2.52 (m, 1 H, CH 2CH=CH2), 4.04-4.07 (m, 1 H, NCH), 5.06-5.11 (m, 2 H, CH2CH=CH 2), 5.12 [br s, 1 H, COC(CH3)=CH 2], 5.28 [br s, 1 H, COC(CH3)=CH 2], 5.65-5.74 (m, 1 H, CH2CH=CH2).
¹³C NMR (126 MHz, CDCl3): δ = 20.6 [COC(CH3)=CH2], 23.8 [COC(CH3)2CH], 27.8 [COC(CH3)2N], 29.1 [COC(CH3)2CH, COC(CH3)2N], 37.5 (CH2CH=CH2), 65.9 (NCH), 80.1 [COC(CH3)2CH], 93.9 [COC(CH3)2N], 116.2 [COC(CH3)=CH2], 118.1 (CH2CH=CH2), 134.8 (CH2 CH=CH2), 142.1 [COC(CH3)=CH2], 166.7 (C=O).
MS (CI, isobutane): m/z (%) = 238.3 (100, [M + H]+).
HRMS (CI, isobutane): m/z calcd for [C14H24NO2]+: 238.1807; found: 238.1806.
1-(3-Allyl-2,2-dimethyl-2,3-dihydrobenzo[1,4]thiazin-4-yl)propenone (6a)
Following GP B, α-methoxy acrylamide 4a (70 mg, 0.27 mmol), allyltrimethylsilane (46 mg, 0.40 mmol), and TiCl4 (101 mg, 0.53 mmol) were used. The crude product was purified by column chromatography (silica gel; n-hexane-EtOAc, 10:1; yield: 49 mg (0.18 mmol, 67%); colorless solid; mp 61 ˚C; R f = 0.45 (n-hexane-EtOAc, 10:1).
IR: 3058, 2975, 2922, 1650, 1477, 1234, 754 cm - ¹.
¹H NMR (500 MHz, CDCl3): δ = 1.44 (s, 6 H, 2 × CH3), 1.93-2.02 (m, 1 H, CH 2CH=CH2), 2.43-2.50 (m, 1 H, CH 2CH=CH2), 4.77 (d, ³ J = 17.0 Hz, 1 H, CH2CH=CH 2), 4.96 (d, ³ J = 10.1 Hz, 1 H, CH2CH=CH 2), 5.07-5.12 (m, 1 H, NCH), 5.69-5.78 (m, 2 H, CH2CH=CH2, COCH=CH2), 6.45-6.48 (m, 1 H, COCH=CH 2), 6.89-6.93 (m, 1 H, o-CHArN), 6.99 (ddd, ³ J = 7.5 Hz, ³ J = 7.5 Hz, 4 J = 1.8 Hz, 1 H, p-CHArN), 7.07 (ddd, ³ J = 7.9 Hz, ³ J = 7.9 Hz, 4 J = 1.1 Hz, 1 H, p-CHArS), 7.10 (dd, ³ J = 7.9 Hz, 4 J = 1.6 Hz, 1 H, o-CHArS).
¹³C NMR (126 MHz, CDCl3): δ = 26.8 (CH3), 32.3 (CH2CH=CH2), 32.5 (CH3), 47.7 [C(CH3)2], 55.6 (NCH), 117.6 (CH2CH=CH2), 123.5 (p-CHArN), 125.7 (p-CHArS), 126.0 (o-CHArS), 128.0 (o-CHArN), 128.7 (COCH=CH2), 129.0 (CHArS), 129.5 (COCH=CH2), 131.4 (CHArN), 134.0 (CH2 CH=CH2), 166.1 (C=O).
MS (CI, isobutane): m/z (%) = 274.1 (100, [M + H]+).
HRMS (CI, isobutane): m/z calcd for [C16H20NOS]+: 274.1266; found: 274.1266.
1-(3-Allyl-2,2-dimethyl-2,3-dihydrobenzo[1,4]thiazin-4-yl)-2-methylpropenone (6b)
Following GP B, α-methoxy acrylamide 4b (0.30 g, 1.1 mmol), allyltrimethylsilane (0.19 g, 1.6 mmol), and TiCl4 (0.41 g, 2.2 mmol) were used. The crude product was purified by column chromatography (silica gel; n-hexane-EtOAc, 7:3); yield: 164 mg (0.57 mmol, 48%); light yellow solid; mp 72 ˚C; R f = 0.55 (n-hexane-EtOAc, 7:3).
IR: 3079, 2987, 2920, 1648, 1477, 1208, 754 cm - ¹.
¹H NMR (500 MHz, CDCl3): δ = 1.43 (s, 3 H, CH3), 1.52 (s, 3 H, CH3), 1.85 [s, 3 H, COC(CH 3)=CH2], 1.95 (ddd, ² J = 14.4 Hz, ³ J = 8.4 Hz, ³ J = 11.6 Hz, 1 H, CH 2CH=CH2), 2.41-2.47 (m, 1 H, CH 2CH=CH2), 4.76 (dd, ² J = 1.2 Hz, ³ J = 17.0 Hz, 1 H, CH2CH=CH 2), 4.92-5.05 (m, 2 H, CH2CH=CH 2, NCH), 5.17-5.21 [m, 2 H, COC(CH3)=CH 2], 5.72 (dddd, ³ J = 5.7 Hz, ³ J = 8.2 Hz, ³ J = 10.2 Hz, ³ J = 17.0 Hz, 1 H, CH2CH=CH2), 6.87-6.92 (m, 2 H, HAr), 6.98-7.02 (m, 1 H, HAr), 7.05-7.08 (m, 1 H, HAr).
¹³C NMR (126 MHz, CDCl3): δ = 20.0 [COC(CH3)=CH2], 27.2 (CH3), 32.9 (CH3), 32.3 (CH2CH=CH2), 48.5 [C(CH3)2], 55.6 (NCH), 117.6 (CH2CH=CH2), 120.8 [COC(CH3)=CH2], 123.2 (CHAr), 125.3 (CHAr), 125.5 (CHAr), 127.3 (CHAr), 128.4 (CArS), 132.7 (CArN), 134.0 (CH2 CH=CH2), 140.6 [COC(CH3)=CH2], 171.2 (C=O).
MS (CI, isobutane): m/z (%) = 288.0 (100, [M + H]+).
HRMS (EI): m/z calcd for C16H20NOS: 287.1344; found: 287.1381.
1-(3-Allyl-2,2-dimethyl-2,3-dihydrobenzo[1,4]oxazin-4-yl)propenone (6c)
Following GP B, α-methoxy acrylamide 4c (67 mg, 0.27 mmol), allyltrimethylsilane (47 mg, 0.41 mmol), and TiCl4 (103 mg, 0.54 mmol) were used. The crude product was purified by column chromatography (silica gel; n-hexane-EtOAc, 8:2); yield: 12 mg (0.05 mmol, 17%); light yellow solid; R f = 0.35 (n-hexane-EtOAc, 8:2). The product was not obtained pure, but it was verified by HRMS and further reaction to 10,10-dimethyl-10,10a-dihydro-1H-9-oxa-4a-azaphenanthren-4-one (8c).
MS (CI, isobutane): m/z (%) = 258.1 (100, [M + H]+).
HRMS (CI, isobutane): m/z calcd for [C16H20NO2]+: 258.1494; found: 258.1494.
1-(3-Allyl-2,2-dimethyl-2,3-dihydrobenzo[1,4]oxazin-4-yl)-2-methylpropenone (6d)
Following GP B, α-methoxy acrylamide 4d (72 mg, 0.28 mmol), allyltrimethylsilane (47 mg, 0.41 mmol), and TiCl4 (131 mg, 0.69 mmol) were used. The crude product was purified by column chromatography (silica gel; n-hexane-EtOAc, 8:2); yield: 60 mg (0.22 mmol, 80%); colorless solid; mp 110-111 ˚C; R f = 0.29 (n-hexane-EtOAc, 8:2).
IR: 3073, 2975, 2925, 2853, 1617, 1495, 1212, 751 cm - ¹.
¹H NMR (500 MHz, CDCl3): δ = 1.31 (s, 3 H, CH3), 1.44 (s, 3 H, CH3), 1.92-2.00 [m, 4 H, COC(CH 3)=CH2, CH 2CH=CH2], 2.38-2.45 (m, 1 H, CH 2CH=CH2), 4.56-4.74 (m, 1 H, NCH), 4.76-4.86 (m, 1 H, CH2CH=CH 2), 4.95-5.00 (m, 1 H, CH2CH=CH 2), 5.23-5.29 [m, 2 H, COC(CH3)=CH 2], 5.72-5.81 (m, 1 H, CH2CH=CH2), 6.76-6.83 (m, 1 H, p-CHArN), 6.85 (dd, ³ J = 8.2 Hz, 4 J = 1.2 Hz, 1 H, o-CHArO), 7.02-7.06 (m, 1 H, p-CHArO), 7.08-7.20 (m, 1 H, o-CHArN).
¹³C NMR (126 MHz, C6D6): δ = 20.4 [COC(CH3)=CH2], 25.2 (CH3), 26.3 (CH3), 32.1 (CH2), 53.9 [C(CH3)2], 77.3 (NCH), 117.2 (o-CHArO), 117.4 (CH2CH=CH2), 118.9 (p-CHArO), 119.7 (CArN)) 123.3 (o-CHArN), 125.0 [COC(CH3)=CH2], 125.8 (p-CHArN), 134.9 (CH2 CH=CH2), 141.3 [COC(CH3)=CH2], 146.1 (CArO), 169.4 (C=O).
MS (CI, isobutane): m/z (%) = 272.2 (100, [M + H]+).
HRMS (CI, isobutane): m/z calcd for [C17H22NO2]+: 272.1651; found: 272.1651.
Lactams 7 and 8; General Procedure (GP C)
α-Allyl acrylamide 5, 6 (1 equiv) synthesized according to GP B and the ruthenium catalyst I (0.05 equiv) in toluene (10 mL) were slowly heated to 70 ˚C until the reaction was complete as controlled by TLC. The solvent was removed under reduced pressure. The product was purified as described below.
1,1,3,3-Tetramethyl-8,8a-dihydro-1 H -thiazolo[3,4- a ]pyridin-5-one (7a)
Following GP C, α-allyl acrylamide 5a (51 mg, 0.21 mmol) and ruthenium catalyst I (10.0 mg, 11 µmol) were used. The crude product was purified by column chromatography (silica gel; n-hexane-EtOAc, 1:1); yield: 37 mg (0.18 mmol, 82%); colorless solid; mp 178 ˚C; R f = 0.34 (n-hexane-EtOAc, 1:1).
IR: 3046, 2964, 2929, 2851, 1661, 1610, 1466, 1403, 1367, 810 cm-¹.
¹H NMR (300 MHz, CDCl3): δ = 1.34 [s, 3 H, SC(CH 3)2CH], 1.45 [s, 3 H, SC(CH 3)2CH], 1.80 [s, 3 H, SC(CH 3)2N], 1.96 [s, 3 H, SC(CH 3)2N], 2.24-2.30 (m, 2 H, CH2), 3.90 (dd, ³ J = 7.9 Hz, ³ J = 11.4 Hz, 1 H, NCH), 5.87 (ddd, ³ J = 9.6 Hz, 4 J = 1.8 Hz, 4 J = 1.8 Hz, 1 H, COCH=CH), 6.53 (ddd, ³ J = 3.7 Hz, ³ J = 5.1 Hz, ³ J = 9.6 Hz, 1 H, COCH=CH).
¹³C NMR (126 MHz, CDCl3): δ = 25.9 (CH2), 26.0 [SC(CH3)2CH], 32.5 [SC(CH3)2CH], 26.8 [SC(CH3)2N], 29.0 [SC(CH3)2N], 50.0 [SC(CH3)2CH], 69.6 (NCH), 71.9 [SC(CH3)2N], 126.9 (COCH=CH), 137.5 (COCH=CH), 165.1 (C=O).
MS (CI, isobutane): m/z (%) = 212.1 (100, [M + H]+).
HRMS (CI, isobutane): m/z calcd for [C11H18NOS]+: 212.1109; found: 212.1107.
1,1,3,3,6-Pentamethyl-8,8a-dihydro-1 H -thiazolo[3,4- a ]pyridin-5-one (7b)
Following GP C, α-allyl acrylamide 5b (51 mg, 0.20 mmol) and ruthenium catalyst I (10.0 mg, 11 µmol) were used. The crude product was purified by column chromatography (silica gel; CH2Cl2); yield: 36 mg (0.16 mmol, 80%); colorless solid; mp 64-65 ˚C; R f = 0.24 (CH2Cl2).
IR: 2960, 2926, 2868, 1669, 1626, 1463, 1402, 1368, 1341, 839 cm-¹.
¹H NMR (300 MHz, CDCl3): δ = 1.30 [s, 3 H, SC(CH 3)2CH], 1.43 [s, 3 H, SC(CH 3)2CH], 1.77 [s, 3 H, SC(CH 3)2N], 1.95 [s, 3 H, SC(CH 3)2N], 1.83-1.84 [m, 3 H, COC(CH 3)=CH], 2.15-2.23 (m, 2 H, CH2), 3.88 (dd, ³ J = 6.8 Hz, ³ J = 12.6 Hz, 1 H, NCH), 6.27-6.29 [m, 1 H, COC(CH3)=CH].
¹³C NMR (126 MHz, CDCl3): δ = 16.6 [COC(CH3)=CH], 25.3 (CH2), 26.0 [SC(CH3)2CH], 32.6 [SC(CH3)2CH], 26.9 [SC(CH3)2N], 29.0 [SC(CH3)2N], 49.8 [SC(CH3)2CH], 70.0 (NCH), 71.9 [SC(CH3)2N], 132.0 [COC(CH3)=CH], 132.7 [COC(CH3)=CH], 166.1 (C=O).
MS (CI, isobutane): m/z (%) = 226.1 (100, [M + H]+).
HRMS (CI, isobutane): m/z calcd for [C12H20NOS]+: 226.1266; found: 226.1265.
1,1,3,3-Tetramethyl-8,8a-dihydro-1 H -oxazolo[3,4- a ]pyridin-5-one (7c)
Following GP C, α-allyl acrylamide 5c (39 mg, 0.18 mmol) and ruthenium catalyst I (8.3 mg, 9 µmol) were used. The crude product was purified by column chromatography (silica gel; n-hexane-EtOAc, 1:1); yield: 22 mg (0.11 mmol, 65%); colorless solid; mp 72-73 ˚C; R f = 0.31 (n-hexane-EtOAc, 1:1).
IR: 2972, 2936, 2854, 1665, 1606, 1422, 1366, 1183 cm-¹.
¹H NMR (500 MHz, CDCl3): δ = 1.22 [s, 3 H, OC(CH 3)2CH], 1.29 [s, 3 H, OC(CH 3)2CH], 1.50 [s, 3 H, OC(CH 3)2N], 1.66 [s, 3 H, OC(CH 3)2N], 2.21-2.25 (m, 2 H, CH2), 3.65 (dd, ³ J = 7.9 Hz, ³ J = 12.2 Hz, 1 H, NCH), 5.85-5.88 (m, 1 H, COCH=CH), 6.51-6.55 (m, 1 H, COCH=CH).
¹³C NMR (126 MHz, CDCl3): δ = 24.0 [OC(CH3)2CH], 25.0 (CH2), 25.9 [OC(CH3)2N], 26.7 [OC(CH3)2CH], 27.7 [OC(CH3)2N], 63.1 (NCH), 80.0 [OC(CH3)2CH], 93.6 [OC(CH3)2N], 126.6 (COCH=CH), 138.0 (COCH=CH), 162.5 (C=O).
MS (CI, isobutane): m/z (%) = 196.0 (100, [M + H]+).
HRMS (ESI): m/z calcd for [C11H18NO2]+: 196.1332; found: 196.1339.
1,1,3,3,6-Pentamethyl-8,8a-dihydro-1 H -oxazolo[3,4- a ]pyridin-5-one (7d)
Following GP C, α-allyl acrylamide 5d (40 mg, 0.17 mmol) and ruthenium catalyst I (8.0 mg, 8 µmol) were used. The crude product was purified by column chromatography (silica gel; n-hexane-EtOAc, 1:1); yield: 30 mg (0.14 mmol, 85%); colorless solid; mp 36-40 ˚C; R f = 0.56 (n-hexane-EtOAc, 1:1).
IR: 2977, 2932, 2844, 1670, 1631, 1420, 1371, 1189 cm-¹.
¹H NMR (500 MHz, CDCl3): δ = 1.22 [s, 3 H, OC(CH 3)2CH], 1.28 [s, 3 H, OC(CH 3)2CH], 1.51 [s, 3 H, OC(CH 3)2N], 1.68 [s, 3 H, OC(CH 3)2N], 1.85-1.86 [m, 3 H, COC(CH 3)=CH], 2.12-2.26 (m, 2 H, CH2), 3.65 (dd, ³ J = 5.9 Hz, ³ J = 13.9 Hz, 1 H, NCH), 6.27-6.29 [m, 1 H, COC(CH3)=CH].
¹³C NMR (126 MHz, CDCl3): δ = 16.3 [COC(CH3)=CH), 24.1 [OC(CH3)2CH], 24.7 (CH2), 25.9 [OC(CH3)2N], 26.8 [OC(CH3)2CH], 27.8 [OC(CH3)2N], 63.5 (NCH), 79.8 [OC(CH3)2CH], 93.6 [OC(CH3)2N], 132.4 [COC(CH3)=CH], 132.6 [COC(CH3)=CH], 163.6 (C=O).
MS (CI, isobutane): m/z (%) = 210.3 (100, [M + H]+).
HRMS (CI, isobutane): m/z calcd for [C12H20NO2]+: 210.1494; found: 210.1494.
10,10-Dimethyl-10,10a-dihydro-1 H -9-thia-4a-azaphenanthren-4-one (8a)
Following GP C, α-allyl acrylamide 6a (27 mg, 0.10 mmol) and ruthenium catalyst I (4.4 mg, 5 µmol) were used. The crude product was purified by column chromatography (silica gel; n-hexane-EtOAc, 1:1); yield: 22 mg (0.09 mmol, 88%); colorless solid; mp 122-124 ˚C; R f = 0.45 (n-hexane-EtOAc, 1:1).
IR: 3053, 2970, 2927, 1669, 1477, 1273, 759 cm - ¹.
¹H NMR (500 MHz, CDCl3): δ = 1.43 (s, 3 H, CH3), 1.44 (s, 3 H, CH3), 2.64 (dddd, ² J = 19.1 Hz, ³ J = 0.9 Hz, ³ J = 2.9 Hz, 4 J = 5.3 Hz, 1 H, CH2), 2.84 (dddd, ² J = 19.1 Hz, ³ J = 2.8 Hz, ³ J = 8.5 Hz, 4 J = 3.1 Hz, 1 H, CH2), 3.91 (dd, ³ J = 2.9 Hz, ³ J = 8.5 Hz, 1 H, NCH), 5.99 (ddd, ³ J = 0.9 Hz, ³ J = 2.8 Hz, ³ J = 10.0 Hz, 1 H, COCH=CH), 6.05 (ddd, ³ J = 10.0 Hz, 4 J = 3.1 Hz, 4 J = 5.3 Hz, 1 H, COCH=CH), 7.02-7.11 (m, 3 H, o + p-CHArS, p-CHArN), 7.54-7.57 (m, 1 H, o-CHArN).
¹³C NMR (126 MHz, CDCl3): δ = 23.7 (CH2), 27.1 (CH3), 28.2 (CH3), 49.6 [C(CH3)2], 62.8 (NCH), 123.8 (CHAr), 125.3 (COCH=CH), 125.5 (CHAr), 126.4 (CHAr), 126.7 (o-CHArN) 127.7 (CArS), 136.1 (CArN), 138.3 (COCH=CH), 162.6 (C=O).
MS (CI, isobutane): m/z (%) = 246.1 (100, [M + H]+).
HRMS (CI, isobutane): m/z calcd for [C14H16NOS]+: 246.0953; found: 246.0952.
3,10,10-Trimethyl-10,10a-dihydro-1 H -9-thia-4a-azaphenanthren-4-one (8b)
Following GP C, α-allyl acrylamide 6b (53 mg, 0.18 mmol) and ruthenium catalyst I (8.7 mg, 9 µmol) were used. The crude product was purified by column chromatography (silica gel; n-hexane-EtOAc, 7:3); yield: 36 mg (0.14 mmol, 77%); colorless solid; mp 97-99 ˚C; R f = 0.43 (n-hexane-EtOAc, 7:3).
IR: 3057, 2960, 2917, 1634, 1408, 1257, 754 cm - ¹.
¹H NMR (500 MHz, CDCl3): δ = 1.41 (s, 3 H, CH3), 1.43 (s, 3 H, CH3), 1.91-1.93 [m, 3 H, COC(CH 3)=CH], 2.52-2.59 (m, 1 H, CH2), 2.77-2.85 (m, 1 H, CH2), 3.87 (dd, ³ J = 3.0 Hz, ³ J = 8.3 Hz, 1 H, NCH), 6.27-6.30 [m, 1 H, COC(CH3)=CH], 7.00-7.09 (m, 3 H, o + p-CHArS, p-CHArN), 7.56-7.59 (m, 1 H, o-CH ArN).
¹³C NMR (126 MHz, CDCl3): δ = 17.1 [COC(CH3)=CH), 23.5 (CH2), 27.1 (CH3), 28.3 (CH3), 49.5 [C(CH3)2], 63.2 (NCH), 123.7, 125.2, 126.4 (o + p-CHArS, p-CHArN), 126.8 (o-CHArN), 127.7 (CArS), 131.2 [COC(CH3)=CH], 132.6 [COC(CH3)=CH], 136.5 (CArN), 164.0 (C=O).
MS (CI, isobutane): m/z (%) = 260.1 (100, [M + H]+).
HRMS (CI, isobutane): m/z calcd for [C15H18NOS]+: 260.1109; found: 260.1109.
10,10-Dimethyl-10,10a-dihydro-1 H -9-oxa-4a-azaphenanthren-4-one (8c)
Following GP C, α-allyl acrylamide 6c (12 mg, 0.05 mmol) and ruthenium catalyst I (2.4 mg, 3 µmol) were used. The crude product was purified by column chromatography (silica gel; n-hexane-EtOAc, 3:2); yield: 6 mg (0.03 mmol, 56%); colorless solid; mp 152-156 ˚C; R f = 0.11 (n-hexane-EtOAc, 3:2).
IR: 3069, 2973, 2928, 2855, 1675, 1492, 1260, 751 cm - ¹.
¹H NMR (500 MHz, CDCl3): δ = 1.23 (s, 3 H, CH3), 1.44 (s, 3 H, CH3), 2.41 (dddd, ² J = 18.4 Hz, ³ J = 2.4 Hz, ³ J = 8.7 Hz, 4 J = 3.4 Hz, 1 H, CH2), 2.63 (dddd, ² J = 18.4 Hz, ³ J = 1.4 Hz, ³ J = 7.2 Hz, 4 J = 4.9 Hz, 1 H, CH2), 3.96 (dd, ³ J = 7.2 Hz, ³ J = 8.9 Hz, 1 H, NCH), 6.04 (ddd, ³ J = 1.4 Hz, ³ J = 2.4 Hz, ³ J = 9.8 Hz, 1 H, COCH=CH), 6.57 (ddd, ³ J = 9.8 Hz, 4 J = 3.4 Hz, 4 J = 4.9 Hz, 1 H, COCH=CH), 6.84 (dd, ³ J = 8.1 Hz, 4 J = 1.4 Hz, 1 H, o-CHArO), 6.90-6.94 (m, 1 H, p-CHArO), 6.99-7.03 (m, 1 H, p-CHArN), 8.27 (dd, ³ J = 8.4 Hz, 4 J = 1.6 Hz, 1 H, o-CHArN).
¹³C NMR (126 MHz, CDCl3): δ = 19.9 (CH3), 25.1 (CH2), 25.9 (CH3), 61.3 (NCH), 76.5 [C(CH3)2], 117.7 (o-CHArO), 120.5 (p-CHArO), 123.5 (o-CHArN), 125.0 (p-CHArN), 125.7 (CArN), 126.3 (COCH=CH), 137.8 (COCH=CH), 145.2 (CArO), 162.8 (C=O).
MS (CI, isobutane): m/z (%) = 230.1 (100, [M + H]+).
HRMS (CI, isobutane): m/z calcd for [C14H16NO2]+: 230.1181; found: 230.1181.
3,10,10-Trimethyl-10,10a-dihydro-1 H -9-oxa-4a-azaphenanthren-4-one (8d)
Following GP C, α-allyl acrylamide 6d (25 mg, 0.09 mmol) and ruthenium catalyst I (4.4 mg, 5 µmol) were used. The crude product was purified by column chromatography (silica gel; n-hexane-EtOAc, 8:2); yield: 17 mg (0.07 mmol, 76%); colorless solid; mp 125-128 ˚C; R f = 0.35 (n-hexane-EtOAc, 8:2).
IR: 3059, 2975, 2928, 2853, 1636, 1490, 1272, 752 cm - ¹.
¹H NMR (500 MHz, CDCl3): δ = 1.21 (s, 3 H, CH3), 1.42 (s, 3 H, CH3), 1.93-1.94 [m, 3 H, COC(CH 3)=CH], 2.31-2.39 (m, 1 H, CH2), 2.50-2.58 (m, 1 H, CH2), 3.93 (dd, ³ J = 6.8 Hz, ³ J = 9.4 Hz, 1 H, NCH), 6.33-6.36 [m, 1 H, COC(CH3)=CH], 6.83 (dd, ³ J = 8.0 Hz, 4 J = 1.4 Hz, 1 H, o-CHArO), 6.91 (ddd, ³ J = 7.5 Hz, ³ J = 7.5 Hz, 4 J = 1.4 Hz, 1 H, p-CHArO), 6.99 (ddd, ³ J = 7.7 Hz, ³ J = 7.7 Hz, 4 J = 1.5 Hz, 1 H, p-CHArN), 8.31 (dd, ³ J = 8.3 Hz, 4 J = 1.4 Hz, 1 H, o-CHArN).
¹³C NMR (126 MHz, CDCl3): δ = 17.4 [COC(CH3)=CH], 19.9 (CH3), 24.9 (CH2), 25.9 (CH3), 61.8 (NCH), 76.3 [C(CH3)2], 117.6 (o-CHArO), 120.4 (p-CHArO), 123.3 (o-CHArN), 124.7 (p-CHArN), 126.7 (CArN), 131.7 [COC(CH3)=CH], 132.4 [COC(CH3)=CH],, 145.3 (CArO), 164.4 (C=O).
MS (CI, isobutane): m/z (%) = 244.1 (100, [M + H]+).
HRMS (CI, isobutane): m/z calcd for [C15H18NO2]+: 244.1338; found: 244.1338.
S -(1,1,3,3-Tetramethyl-5-oxohexahydrothiazolo[3,4- a ]pyridin-7-yl) Thioacetate (9)
The unsaturated lactam 7a (22 mg, 0.10 mmol), an excess of thioacetic acid (0.2 mL, 2.82 mmol), and a small amount of AIBN were heated at 100 ˚C for 6 h. The excess of thioacetic acid was then removed under reduced pressure at r.t. According to the ¹H NMR spectrum, the diastereomeric ratio was ≥95:5. The crude product was filtered through a short silica gel column with EtOAc as eluent; yield: 27 mg (0.09 mmol, 90%); colorless oil.
IR: 2979, 2929, 1693, 1649, 1399, 1364, 1308, 1114, 626 cm-¹.
¹H NMR (500 MHz, CDCl3): δ = 1.30 [s, 3 H, SC(CH 3)2CH], 1.36 [s, 3 H, SC(CH 3)2CH], 1.75 [s, 3 H, SC(CH 3)2N], 1.81 (ddd, ² J = 13.6 Hz, ³ J = 11.3 Hz, ³ J = 3.4 Hz, 1 H, NCHCH 2), 1.96 [s, 3 H, SC(CH 3)2N], 1.99-2.04 (m, 1 H, NCHCH 2), 2.34 (s, 3 H, SCOCH3), 2.45 (ddd, ² J = 17.7 Hz, ³ J = 2.4 Hz, 4 J = 2.4 Hz, 1 H, COCH 2CHS), 2.80 (dd, ² J = 17.7 Hz, ³ J = 5.8 Hz, 1 H, COCH 2CHS), 3.80 (dd, ³ J = 4.0 Hz, ³ J = 11.3 Hz, 1 H, NCHCH2), 4.07-4.10 (m, 1 H, COCH2CHS).
¹³C NMR (126 MHz, CDCl3): δ = 25.3 [SC(CH3)2CH], 25.7 [SC(CH3)2CH], 29.2 [SC(CH3)2N], 29.3 (NCHCH2), 30.9 (SCOCH3), 32.0 [SC(CH3)2N], 37.1 (COCH2 CHS), 39.2 (COCH2CHS), 50.5 [SC(CH3)2CH], 68.0 (NCHCH2), 71.7 [SC(CH3)2N], 167.3 (C=O), 194.4 (SC=O).
MS (CI, isobutane): m/z (%) = 288.0 (100, [M + H]+).
HRMS (CI, isobutane): m/z calcd for [C13H22NO2S2]+: 288.1092; found: 288.1092.
Acknowledgment
We are indebted to Ludmila Hermann for the preparative assistance. The ruthenium catalyst I was generously supplied to us by Evonik Degussa GmbH and the silica gel by Grace GmbH & Co. KG. K. S. and K. J. gratefully acknowledge the Heinz Neumüller-Stiftung for a doctoral fellowship.
- 1a
Navickiene HMD.Alecio AC.Kato MJ.Bolzani VD.Young MCM.Cavalheiro AJ.Furlan M. Phytochemistry 2000, 55: 621 - 1b
Chen JJ.Chang YL.Teng CM.Su CC.Chen IS. Planta Med. 2002, 68: 790 - 1c
Chen JJ.Duh CY.Huang HY.Chen IS. Helv. Chim. Acta 2003, 86: 2058 - 1d
Tsai IL.Lee FP.Wu CC.Duh CY.Ishikawa T.Chen JJ.Chen YC.Seki H.Chen IS. Planta Med. 2005, 71: 535 - 1e
Cardona W.Quinones W.Robledo S.Velez ID.Murga J.Garcia-Fortanet J.Carda M.Cardona D.Echeverri F. Tetrahedron 2006, 62: 4086 - 1f
Ding PL.Liao ZX.Huang H.Zhou P.Chen DF. Bioorg. Med. Chem. Lett. 2006, 16: 1231 - 2a
Sundberg RJ.Bukowick PA.Holcombe FO. J. Org. Chem. 1967, 32: 2938 - 2b
Hua DH.Zhang F.Chen J. J. Org. Chem. 1994, 59: 5084 - 2c
Amat M.Pérez M.Llor N.Bosch J. Org. Lett. 2002, 4: 2787 - 2d
Chandra KL.Chandrasekhar M.Singh VK. J. Org. Chem. 2002, 67: 4630 - 2e
Fuwa H.Kaneko A.Sugimoto Y.Tomita T.Iwatsubo T.Saski M. Heterocycles 2006, 70: 101 - 2f
Maio DG.Tardella PA. Gazz. Chim. Ital. 1964, 94: 590 - 3a
Flemming A. Br. J. Exp. Pathol. 1929, 10: 226 - 3b
Penicilline (C),
In Römpp Online V. 3.1
Thieme;
Stuttgart:
2008. RD-16-00773
- 3c
Dalhoff A. Infection 1979, 7: 294 - 3d
Holzgrabe U. Pharm. Unserer Zeit 2006, 35: 410 - 4a
Gillies PS.Dunn CJ. Drugs 2000, 60: 333 - 4b
Lohray BB.Bhusan V.Rao BP.Medhavan GR.Murali N.Rao KN.Reddy AK.Rajesh BM.Reddy PG.Chakrabarti R.Vikramadithyan RK.Rajagopalan R.Mamidi RNVS.Jajoo HK.Subramanian S. J. Med. Chem. 1998, 41: 1619 - 5
Elander RP. Appl. Microbiol. Biotech. 2003, 61: 385 - 6a
Matsumoto Y.Tsuzuki R.Matsuhisa A.Takayama K.Yoden T.Uchida W.Asano M.Fujita S.Yanagisawa I.Fujikura T. Chem. Pharm. Bull. 1996, 44: 103 - 6b
Kobayashi T.Strobeck M.Schwartz A.Mori Y. Eur. J. Pharmacol. 1997, 332: 313 - 6c
Matsumoto Y.Tsuzuki R.Matsuhisa A.Yoden T.Yamagiwa Y.Yanagisawa I.Shibanuma T.Nohira H. Bioorg. Med. Chem. 2000, 8: 393 - 6d
Okuyama K.Kiuchi S.Okamoto M.Narita H.Kudo Y. Eur. J. Pharmacol. 2000, 398: 209 - 6e
Cecchetti V.Calderone V.Tabarrini O.Sabatini S.Filipponi E.Testai L.Spogli R.Martinotti E.Fravolini A. J. Med. Chem. 2003, 46: 3670 - 7a
Trapani G.Reho A.Morlacchi F.Latrofa A.Marchini P.Venturi F.Cantalamessa F. Farmaco, Ed. Sci. 1985, 40: 369 - 7b
Armenise D.Trapani G.Stasi F.Morlacchi F. Arch. Pharm. (Weinheim, Ger.) 1998, 331: 54 - 8a
Hayakawa I.Atarashi S.Yokohama S.Imamura M.Sakano K.Furukawa M. Antimicrob. Agents Chemother. 1986, 29: 163 - 8b
Atarashi S.Tsurumi H.Fujiwara T.Hayakawa I. J. Heterocycl. Chem. 1991, 28: 329 - 8c
Hirata T.Saito H.Tomioka H.Sato K.Jidoi J.Hosoe K.Hidaka T. Antimicrob. Agents Chemother. 1995, 39: 2295 - 9
Martens J.Offermanns H.Scherberich P. Angew. Chem., Int. Ed. Engl. 1981, 20: 668 ; Angew. Chem. 1981, 93, 680 - 10
Weber M.Jakob J.Martens J. Liebigs Ann. Chem. 1992, 1 - 11
Gröger H.Martens J. Sulf. Lett. 1996, 19: 197 - 12
Watzke M.Schulz K.Johannes K.Ullrich P.Martens J. Eur. J. Org. Chem. 2008, 3859 - 13
Böhme H.Hartke K. Chem. Ber. 1963, 96: 600 - 14
Schwarze W.Drauz K.Martens J. Chem.-Ztg. 1987, 111: 149 - 15
Hosomi A.Sakurai H. Tetrahedron Lett. 1976, 1295 - 16a
Hart DJ.Tsai Y.-M. Tetrahedron Lett. 1981, 22: 1567 - 16b
Kraus GA.Neuenschwander K. J. Chem. Soc., Chem. Commun. 1982, 134 - 16c
Kano S.Yuasa Y.Shibuya S. Heterocycles 1987, 26: 373 - 16d
Herborn C.Zietlow A.Steckhan E. Angew. Chem., Int. Ed. Engl. 1989, 28: 1399 ; Angew. Chem. 1989, 101, 1392 - 17a
Rodriguez S.Castillo E.Carda M.Marco JA. Tetrahedron 2002, 58: 1185 - 17b
Chen Y.Zhang H.Nan F. J. Comb. Chem. 2004, 6: 684 - 17c
Deiters A.Pettersson M.Martin SF. J. Org. Chem. 2006, 71: 6547 - 17d
Liu G.Tai W.-Y.Li Y.-L.Nan F.-J. Tetrahedron Lett. 2006, 47: 3295 - 17e
Fiorelli C.Savoia D. J. Org. Chem. 2007, 72: 6022
References
In former investigations using similar substrates, a first-generation Grubbs catalyst showed less activity.¹²
19CCDC 706274 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
- 1a
Navickiene HMD.Alecio AC.Kato MJ.Bolzani VD.Young MCM.Cavalheiro AJ.Furlan M. Phytochemistry 2000, 55: 621 - 1b
Chen JJ.Chang YL.Teng CM.Su CC.Chen IS. Planta Med. 2002, 68: 790 - 1c
Chen JJ.Duh CY.Huang HY.Chen IS. Helv. Chim. Acta 2003, 86: 2058 - 1d
Tsai IL.Lee FP.Wu CC.Duh CY.Ishikawa T.Chen JJ.Chen YC.Seki H.Chen IS. Planta Med. 2005, 71: 535 - 1e
Cardona W.Quinones W.Robledo S.Velez ID.Murga J.Garcia-Fortanet J.Carda M.Cardona D.Echeverri F. Tetrahedron 2006, 62: 4086 - 1f
Ding PL.Liao ZX.Huang H.Zhou P.Chen DF. Bioorg. Med. Chem. Lett. 2006, 16: 1231 - 2a
Sundberg RJ.Bukowick PA.Holcombe FO. J. Org. Chem. 1967, 32: 2938 - 2b
Hua DH.Zhang F.Chen J. J. Org. Chem. 1994, 59: 5084 - 2c
Amat M.Pérez M.Llor N.Bosch J. Org. Lett. 2002, 4: 2787 - 2d
Chandra KL.Chandrasekhar M.Singh VK. J. Org. Chem. 2002, 67: 4630 - 2e
Fuwa H.Kaneko A.Sugimoto Y.Tomita T.Iwatsubo T.Saski M. Heterocycles 2006, 70: 101 - 2f
Maio DG.Tardella PA. Gazz. Chim. Ital. 1964, 94: 590 - 3a
Flemming A. Br. J. Exp. Pathol. 1929, 10: 226 - 3b
Penicilline (C),
In Römpp Online V. 3.1
Thieme;
Stuttgart:
2008. RD-16-00773
- 3c
Dalhoff A. Infection 1979, 7: 294 - 3d
Holzgrabe U. Pharm. Unserer Zeit 2006, 35: 410 - 4a
Gillies PS.Dunn CJ. Drugs 2000, 60: 333 - 4b
Lohray BB.Bhusan V.Rao BP.Medhavan GR.Murali N.Rao KN.Reddy AK.Rajesh BM.Reddy PG.Chakrabarti R.Vikramadithyan RK.Rajagopalan R.Mamidi RNVS.Jajoo HK.Subramanian S. J. Med. Chem. 1998, 41: 1619 - 5
Elander RP. Appl. Microbiol. Biotech. 2003, 61: 385 - 6a
Matsumoto Y.Tsuzuki R.Matsuhisa A.Takayama K.Yoden T.Uchida W.Asano M.Fujita S.Yanagisawa I.Fujikura T. Chem. Pharm. Bull. 1996, 44: 103 - 6b
Kobayashi T.Strobeck M.Schwartz A.Mori Y. Eur. J. Pharmacol. 1997, 332: 313 - 6c
Matsumoto Y.Tsuzuki R.Matsuhisa A.Yoden T.Yamagiwa Y.Yanagisawa I.Shibanuma T.Nohira H. Bioorg. Med. Chem. 2000, 8: 393 - 6d
Okuyama K.Kiuchi S.Okamoto M.Narita H.Kudo Y. Eur. J. Pharmacol. 2000, 398: 209 - 6e
Cecchetti V.Calderone V.Tabarrini O.Sabatini S.Filipponi E.Testai L.Spogli R.Martinotti E.Fravolini A. J. Med. Chem. 2003, 46: 3670 - 7a
Trapani G.Reho A.Morlacchi F.Latrofa A.Marchini P.Venturi F.Cantalamessa F. Farmaco, Ed. Sci. 1985, 40: 369 - 7b
Armenise D.Trapani G.Stasi F.Morlacchi F. Arch. Pharm. (Weinheim, Ger.) 1998, 331: 54 - 8a
Hayakawa I.Atarashi S.Yokohama S.Imamura M.Sakano K.Furukawa M. Antimicrob. Agents Chemother. 1986, 29: 163 - 8b
Atarashi S.Tsurumi H.Fujiwara T.Hayakawa I. J. Heterocycl. Chem. 1991, 28: 329 - 8c
Hirata T.Saito H.Tomioka H.Sato K.Jidoi J.Hosoe K.Hidaka T. Antimicrob. Agents Chemother. 1995, 39: 2295 - 9
Martens J.Offermanns H.Scherberich P. Angew. Chem., Int. Ed. Engl. 1981, 20: 668 ; Angew. Chem. 1981, 93, 680 - 10
Weber M.Jakob J.Martens J. Liebigs Ann. Chem. 1992, 1 - 11
Gröger H.Martens J. Sulf. Lett. 1996, 19: 197 - 12
Watzke M.Schulz K.Johannes K.Ullrich P.Martens J. Eur. J. Org. Chem. 2008, 3859 - 13
Böhme H.Hartke K. Chem. Ber. 1963, 96: 600 - 14
Schwarze W.Drauz K.Martens J. Chem.-Ztg. 1987, 111: 149 - 15
Hosomi A.Sakurai H. Tetrahedron Lett. 1976, 1295 - 16a
Hart DJ.Tsai Y.-M. Tetrahedron Lett. 1981, 22: 1567 - 16b
Kraus GA.Neuenschwander K. J. Chem. Soc., Chem. Commun. 1982, 134 - 16c
Kano S.Yuasa Y.Shibuya S. Heterocycles 1987, 26: 373 - 16d
Herborn C.Zietlow A.Steckhan E. Angew. Chem., Int. Ed. Engl. 1989, 28: 1399 ; Angew. Chem. 1989, 101, 1392 - 17a
Rodriguez S.Castillo E.Carda M.Marco JA. Tetrahedron 2002, 58: 1185 - 17b
Chen Y.Zhang H.Nan F. J. Comb. Chem. 2004, 6: 684 - 17c
Deiters A.Pettersson M.Martin SF. J. Org. Chem. 2006, 71: 6547 - 17d
Liu G.Tai W.-Y.Li Y.-L.Nan F.-J. Tetrahedron Lett. 2006, 47: 3295 - 17e
Fiorelli C.Savoia D. J. Org. Chem. 2007, 72: 6022
References
In former investigations using similar substrates, a first-generation Grubbs catalyst showed less activity.¹²
19CCDC 706274 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Scheme 1 Precursors used for the synthesis of 1
Scheme 2 Synthesis of lactams 7 and 8. Reagents and conditions: (a) (i) CH2C(R)COCl, CH2Cl2, 0-5 ˚C, (ii) r.t., 3 h; (b) (i) MeOH, Et3N, CH2Cl2, 0-5 ˚C, (ii) r.t., 1 h, 42-86%; (c) CH2=CHCH2SiMe3, TiCl4, CH2Cl2, -30 ˚C, 1.5 h, (ii) r.t., 18 h, 17-96%; (d) catalyst I, toluene, up to 70 ˚C, 56-88%.
Figure 1 Used ruthenium catalyst I
Figure 2 ORTEP representation of lactam 8a in the solid state
Scheme 3 Addition of thioacetic acid on Michael acceptor 7a. Reagents and conditions: (a) CH3COSH, AIBN, 100 ˚C, 6 h, 90%.