DMT - As easy as ABC
(Rated as: excellent)
Well, maybe not as easy as it sounds - ABC is short for Anionic Benzyne Cyclization... It is a very novel and elegant synthesis though, and can also be used to synthesize 4- and 5-substituted DMT analogs.
Please tell me if I have made any logical errors when dissecting the experimental from the article to write a streamlined DMT synthesis from it, I have never seen such a recursive, self-referencing writing style before...
Synthesis of Functionalized Indole- and Benzo-Fused Heterocyclic Derivatives through Anionic Benzyne Cyclization
José Barluenga, Prof. Dr., Francisco J. Fañanás, Dr., Roberto Sanz, Dr., Yolanda Fernández
Chemistry - A European Journal, 8(9), 2034-2046 (2002) (../rhodium/pdf /tryptamines.
The development of a new method for the regioselective synthesis of functionalized indoles and six-membered benzo-fused N-, O-, and S-heterocycles is reported. The key step involves the generation of a benzyne-tethered vinyl or aryllithium compound that undergoes a subsequent intramolecular anionic cyclization. Reaction of the organolithium intermediates with selected electrophiles allows the preparation of a wide variety of indole, tetrahydrocarbazole, dihydrofenantridine, dibenzopyran, and dibenzothiopyran derivatives. Finally, the application of this strategy to the appropriate starting materials allows the preparation of some tryptamine and serotonin analogues.
Experimental - Synthesis of DMT
Scheme I. i) H2C=N+Me2I-, THF, 67°C; ii) DIBAL-H (1.5 equiv), cat. [NiCl2(dppp)], toluene, 20°C.
A solution of 2-fluoroaniline (6.93 g, 62.5 mmol) in THF (60 mL) was treated with BuLi (10 mL, 2.5 M solution in hexanes, 25 mmol) at -50°C. The reaction was stirred for 30 min at this temperature and then allowed to reach 20°C, and stirring was continued for 45 min. The reaction was re-cooled to -50°C and allyl bromide (3.03 g, 25 mmol) was added. After 15 min at this temperature, the reaction was allowed to warm up and stirring was continued for 5 h. The mixture was hydrolyzed with water, extracted with ethyl acetate (3×30 mL), and the combined organic layers were washed with saturated aqueous Na2CO3 solution, and dried over anhydrous Na2SO4. The solvents were removed under vacuum and the residue was purified by silica gel column chromatography to afford N-Allyl-2-fluoroaniline (2.83 g, 75%) as an orange oil. Rf=0.35 (hexane/ethyl acetate 30:1).
1H NMR (CDCl3, 80 MHz): =7.2-6.5 (m, 4 H), 6.2-5.7 (m, 1 H), 5.4-5.0 (m, 2 H), 4.0 (br s, 1 H), 3.8 (d, J=4.0 Hz, 2 H);
13C NMR (CDCl3, 20.2 MHz): =151.6 (d, J=238.2 Hz), 136.5 (d, J=11.2 Hz), 134.9, 124.4 (d, J=3.0 Hz), 116.6 (d, J=6.7 Hz), 116.0, 114.2 (d, J=18.5 Hz), 112.3 (d, J=2.6 Hz), 45.9;
MS (70 eV, EI): m/z (%): 151 (100) [M]+
A solution of 2-Fluoro-N-allylaniline (3.8 g, 25 mmol) in THF (30 mL) was treated with BuLi (10 mL, 2.5 M solution in hexanes, 25 mmol) at -50°C. The reaction mixture was stirred for 15 min and was then allowed to warm up to 20°C, and stirring was continued for 45 min. The reaction mixture was cooled to -50°C and 2,3-dibromopropene (5.0 g, 25 mmol) was added. After 15 min at this temperature, the reaction was allowed to warm up and stirring was continued for 5 h. The mixture was hydrolyzed with water, extracted with ethyl acetate (3×30 mL), and the combined organic layers were washed with saturated aqueous Na2CO3 and dried over anhydrous Na2SO4. The solvents were removed under vacuum and the residue was purified by silica gel column chromatography to afford 1b (4.77 g, 71%) as a colorless oil. Rf=0.28 (hexane/ethyl acetate 50:1).
1H NMR (CDCl3, 200 MHz): =7.15-6.8 (m, 4 H), 6.05-5.8 (m, 2 H), 5.7-5.6 (m, 1 H), 5.35-5.2 (m, 2 H), 4.1 (s, 2 H), 3.9 (d, J=5.6 Hz, 2 H);
13C NMR (CDCl3, 50.5 MHz): =155.6 (d, J=244.0 Hz), 138.1 (d, J=8.5 Hz), 135.2, 131.2, 125.1 (d, J=3.0 Hz), 122.1 (d, J=7.5 Hz), 121.1 (d, J=2.9 Hz), 118.5, 118.1, 117.4 (d, J=21.0 Hz), 60.1 (d, J=4.6 Hz), 55.5 (d, J=4.0 Hz);
MS (70 eV, EI): m/z (%): 271 (33) [M+2]+, 269 (33) [M]+, 164 (100)
A solution of amine 1b (0.54 g, 2 mmol) in THF (15 mL) was treated with t-BuLi (4.7 mL, 1.5 M solution in pentane, 7 mmol) at -110 °C. The reaction mixture was stirred for 15 min at this temperature, and the cooling bath was then removed to allow the reaction to warm up to room temperature. The mixture was re-cooled to -78°C, water (0.05 mL, 3 mmol) was added, followed by N,N-dimetylmethyleneammonium iodide (0.41 g, 2.2 mmol) and the reaction mixture was heated at reflux for 3 h (monitored by TLC). The mixture was hydrolyzed with water and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over anhydrous Na2SO4 and the solvent was removed under vacuum to yield a residue.
The residue and [NiCl2(dppp)] (0.03g*, 0.08 mmol) were dissolved in toluene (6 mL). DIBAL-H (1.5 equiv, 2 mL, 1.5 M solution in toluene, 3.0 mmol) was added at 0°C and the temperature was increased to room temperature. After stirring at the same temperature for 2 h, the mixture was treated with 0.5 M NaOH (2 mL) and Et2O (9 mL) for 1 h and it was then dried directly over MgSO4. After evaporation of the solvent, the residue was purified by flash column chromatography (hexane/ethyl acetate) to afford product 11 (0.19 g, 51 %) as a yellow oil.*
1H NMR (CDCl3, 400 MHz): =8.2 (br s, 1 H), 7.6 (d, J=7.6 Hz, 1 H), 7.35 (d, J=7.6 Hz, 1 H), 7.2 (t, J=7.6 Hz, 1 H), 7.1 (t, J=7.6 Hz, 1 H), 7.0 (s, 1 H), 3.0-2.9 (m, 2 H), 2.7-2.62 (m, 2 H), 2.3 (s, 6 H);
13C NMR (CDCl3, 50.5 MHz): =136.3, 127.4, 121.8, 121.4, 119.1, 118.7, 114.3, 111.1, 60.3, 45.4, 23.7;
MS (70 eV, EI): m/z (%): 188 (6) [M]+, 58 (100).
* Also given as [NiCl2(dppp)] (0.004 g, 0.08 mmol) in the text, so recalculate the molar weight to be sure.
* Footnote: We could not recrystallize the solid compound 11a. See: M. S. Fish, N. M. Johnson, E. C. Horning, J. Am. Chem. Soc. 78, 3668 (1956).