Checked by Shaowo Liang and Leo A. Paquette.
1. Procedure
B.
N-(tert-Butoxycarbonyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one A 1-L, three-necked, round-bottomed flask is equipped with a nitrogen inlet,
mechanical stirrer, thermometer, and a pressure-equalizing dropping funnel (Note
8). The flask is charged with
93 g (210 mmol) of lead tetraacetate (Note
9) and
250 mL of glacial acetic acid. Stirring is started, the flask is immersed in an
ice-water bath, and the funnel is charged with a solution of
61 g (200 mmol) of N-(tert-butoxycarbonyl)-6,7-dimethoxy-1-methylene-1,2,3,4-tetrahydroisoquinoline (Note
10) in
250 mL of methylene chloride. This solution is added at such a rate that a temperature of 19–23°C is maintained throughout the addition, typically over a period of 15 to 20 min. The
cooling bath is removed, and the mixture is stirred at room temperature for 1 hr.
Glycerol (4 mL) is added to quench unreacted
lead tetraacetate, and the mixture is stirred for an additional 10 min.
The mixture is poured into 750 mL of water in a
2-L separatory funnel and shaken thoroughly. The phases are separated, and the aqueous phase is extracted with two
100-mL portions of methylene chloride. The combined organic layers are washed with 700 mL of water, followed by successive
100-mL portions of saturated aqueous sodium bicarbonate until no further effervescence is observed. The organic layer is dried over
magnesium sulfate, filtered, and evaporated at reduced pressure to give a yellow-orange solid, which is dissolved in
100 mL of boiling acetone and allowed to cool slowly to room temperature, then kept overnight at −20°C. Filtration affords a cream-colored solid in a yield of
51.2–52.2 g (Note
11), (Note
12). A second crop is obtained by evaporation of the mother liquors, dissolution in a minimal amount of boiling
acetone, cooling and seeding. The total yield is brought to
58–59 g (
90–92%).
2. Notes
1. The glassware is dried in an
oven at 110°C and assembled while still hot, then allowed to cool while a slow stream of
nitrogen is passed through the apparatus.
3. The submitters used
J. T. Baker Chemical Company hydrocarbon-stabilized chloroform containing 0.015% amylene stabilizer. The checkers used
chloroform of comparable quality purchased from Aldrich Chemical Company, Inc.
5. The addition typically took 1.5 to 2 hr. The bubbler on the
nitrogen line used to flush the flask is conveniently used to monitor the evolution of
carbon dioxide as the reaction proceeds.
7. If desired, the material can be recrystallized from
methanol; under these circumstances,
146–149 g of white solid, mp
101–102°C, is returned. The spectral characteristics of recrystallized material are as follows:
1H NMR (300 MHz, CDCl
3) δ: 1.49 (s, 9 H), 2.78 (t, 2 H, J = 5.9), 3.77 (t, 2 H, J = 5.9), 3.86 (s, 3 H), 3.89 (s, 3 H), 5.31 (s, 1 H), 5.50 (s, 1 H), 6.56 (s, 1 H), 7.11 (s, 1 H); IR (KBr) cm
−1: 1690, 1630, 1605, 1510, 1390, and 1170;
13C NMR (75 MHz, CDCl
3) δ: 28.38, 28.96, 43.51, 55.89, 56.02, 80.47, 101.86, 107.46, 110.77, 124.84, 127.72, 139.99, 147.51, 149.22, 153.83. Anal. Calcd. for C
17H
23NO
4: C, 66.86; H, 7.59; N, 4.59. Found: C, 67.02; H, 7.48; N, 4.65.
8. The glassware is assembled hot under
nitrogen as for the previous step. The nitrogen inlet and stirrer are mounted on a
Claisen adapter, and the thermometer is removed during the flushing period, then reinserted.
9. The submitters used
lead tetraacetate from Aldrich Chemical Company, Inc., which was dried under reduced pressure at room temperature for 10 min prior to use to remove any
acetic acid present. Alternatively,
lead tetraacetate still containing
acetic acid may be used successfully if a slight excess is used.
10. If crude material containing
tert-butyl alcohol and unreacted pyrocarbonate is used in this step, the amount of starting material present is calculated based on the mass balance for the first step, assuming a quantitative conversion, and 1.05 equivalents of
lead tetraacetate are used. The checkers used only pure material and advise against carrying forward less pure carbamate.
11. This material may be used directly in the following step. If desired, the material can be recrystallized from
acetone, mp
116.5–118°C. The spectral characteristics of the recrystallized material are as follows:
1H NMR (300 MHz, CDCl
3) δ: 1.52 (s, 9 H), 3.14 (t, 2 H, J = 6.0), 3.84 (s, 6 H), 3.92 (s, 2 H), 4.18 (t, 2 H, J = 6.0), 6.56 (s, 1 H), 6.57 (s, 1 H); IR (KBr) cm
−1: 1715, 1610, 1525, 1370, 1255, 1110, and 1060;
13C NMR (75 MHz, CDCl
3) δ: 28.03, 32.83, 43.42, 45.21, 55.94, 55.97, 83.18, 113.25, 114.28, 121.92, 127.09, 147.41, 148.38, 152.08, 171.33. Anal. Calcd. for C
17H
23NO
5: C, 63.54; H, 7.21; N, 4.36. Found: C, 63.36; H, 7.30; N, 4.16.
12. If insufficient
lead tetraacetate is used in the oxidation, unoxidized starting enamide is hydrolyzed during the workup to
tert-butyl 2-(2-acetyl-3,4-dimethoxyphenyl) ethyl carbamate, mp
111.5–112.5°C (cf. ref. in (Note
2)):
1H NMR (270 MHz, CDCl
3) δ: 1.42 (s, 9 H), 2.58 (s, 3 H), 3.03 (t, 2 H), 3.37 (q, 2 H), 3.92 (s, 3 H), 6.76 (s, 1 H), 7.23 (s, 1 H); IR (FTIR) cm
−1: 1707, 1674, 1604, 1517, 1266, 1212, 1152. Anal. Calcd for C
17H
25NO
5: C, 63.13; H, 7.79; N, 4.33. Found: C, 63.24; H, 7.91; N, 4.28. The hydrolyzed material co-migrates with the oxidation product in a variety of TLC systems, and also co-crystallizes with it. It is, however, removed during the
trifluoroacetic acid (TFA) cleavage to form the benzazepinone (Step C). The presence of any hydrolyzed material is readily detected by the presence of the acetyl resonance (δ 2.58) in the NMR spectrum.

13. After approximately
25 mL of the trifluoroacetic acid have been added, gas evolution begins. This can be quite vigorous if the temperature is not kept below 10°C.
14. The progress of the reaction can be monitored by thin layer chromatography on silica gel plates, using a
95:5:0.5 mixture of chloroform:methanol:concentrated ammonium hydroxide as the developing solvent.
15. Foaming can be quite vigorous, especially if the reaction mixture is not washed first with water prior to the use of
sodium bicarbonate solution.
16. A small second crop of impure material can be obtained from the mother liquors.
17. The product exhibited the following spectral characteristics:
1H NMR (300 MHz, CDCl
3) δ: 3.03 (t, 2 H, J = 6.0), 3.52–3.60 (m, 2 H), 3.75 (s, 2 H), 3.83 (s, 3 H), 3.84 (s, 3 H), 6.34 (br s, 1 H), 6.59 (s, 1 H), 6.62 (s, 1 H);
13C NMR (75 MHz, CDCl
3) δ: 33.03, 40.62, 41.71, 55.77 (2C), 112.96, 113.53, 123.19, 128.39, 147.09, 147.72, 174.49; IR (KBr) cm
−1: 1675, 1220, 1125, 1100, and 1010.
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
Several approaches to the synthesis of the tetrahydrobenzazepine ring system have been described,
7 and excellent methods exist for the preparation of aryl substituted tetrahydrobenzazepines.
6 However, benzazepines that are either unsubstituted or alkyl-substituted on the azepine ring are much less readily obtainable. For instance, the benzazepinone, synthesized by this procedure, was originally isolated, in low yield, from the mixture of photoproducts obtained from the irradiation of
N-[3-(3,4-dimethoxyphenyl)]propyl chloroacetamide.
8 9 Preparative approaches to the benzazepinones have required multiple steps starting from an
N-phenylethylacetamide and involving chloromethylation, cyanide displacement, nitrile solvolysis, hydrolysis to the amino acid and cyclization.
10 11 The 1-alkyl derivatives are subsequently prepared by alkylation of the parent compound.
12 The current procedure reduces the preparation of the tetrahydrobenzazepinone ring system to two straightforward steps.
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