Bromocriptine to Lysergamides

Maya · Wed Mar 02, 2005 9:56 pm

There has been a little talk of it but I have still not heard of anybody accomplishing this synth yet:

Bromocriptine hydrolysis to bromolysergic acid amidation to bromoLSD
grignard rxn to LSD

Bromocriptine is easily available and this would be a three step reaction. has it been done succesfully?

Nicodem · Thu Mar 03, 2005 12:10 am

You can not do a Grignard reaction on "bromoLSD".
It has an acidic hydrogen (the indolic NH) and an electrophylic amide (the -CO-NEt2) and even without these, the double bond would get isomerised anyway.

Maya · Thu Mar 03, 2005 6:03 pm

If Charge transfer complex formation is a problem with the grignard rxn of bromolsd then maybe a protecting group like BOC can be added to the indolic NH and later deprotected with triflouroacetic acid. bromolysergic methyl ester might also be used instead of the amide if the amide is too electrophilic

Maya · Thu Mar 03, 2005 6:12 pm

How about the use of ( in order of decreasing activity) for the de-halogenation?:

Red-Al > N-Selectride > K-Selectride > L-Selectride >> DIBAL-H, MeLi, n-BuLi;
The rate of dehalogenation may be boosted by adding 4a molecular sieve.

Maya · Thu Mar 03, 2005 6:31 pm

http://journal.kcsnet.or.kr/publi/bul/bu00n2/211.pdf

de-halogenation of nitrogen heterocycles, any comments?

Maya · Thu Mar 03, 2005 9:06 pm

Si-Tin Hydride

http://www.silicycle.com/html/english/products/produit_detail.php?pro_id=179

Product Data Sheet
Part Number: R72530B
Loading: 0.6 mmol / g
Particle Size: 40 - 63 µm
Pore Size: 60
Specific surface area: 500 m²/g
Description: Reducing agent

Technical Information

Silica-bound tin hydride is a highly selective reagent for dehalogenation or reduction of alkyl halides. Dehalogenation of 1-bromoadamantane 92% yield by NMR after 4 h. Solution phase organotin compounds are highly toxic and the silica support allows them to be safely used and remove the risk of tin contamination in the final product.

Tin hydride can also be used for the ring enlargement of cyclohexadienones, in the Barton-McCombie deoxygenation and in the Giese reaction.

--------------------------------------------------------------------------------

J. Org. Chem., 56 (1991) 5971

Sample Procedures

Dehalogenation of Iodooctane: Mix the halide (1.0 eq.) with Si-Tin Hydride in anhydrous diethyl ether at reflux under argon. 60% yield with 1 eq. of Si-Tin Hydride after 1 h.

Dehalogenation of 1-bromoadamantane: Mix the halide (2.0 eq.) with Si-Tin Hydride (2.0 eq.) and a catalyic amount of AIBN (0.02 eq.) in anhydrous benzene at 60°C under argon for 4 h. 92% yield.

Maya · Thu Mar 03, 2005 11:05 pm

Okay, finally, can anyone confirm this. it looks like the correct reagent to use in the dehalogenation of bromoLA would bee Tributyltin hydride.

This would be selective for the Br without affecting the indolic NH since it has been used to debrominate bromoindole.

BTW, I still think a regular grignard might still work:

Alkylation of Indole Grignards With 2-(Dimethylamino)-Ethyl Chloride
Chemistry and Industry 1388-89 (1964)
HTML by Rhodium
The reaction of indolylmagnesium iodide with substituted alkyl halides, e.g., the nitriles Cl(CH2)nCN and chloroacetyl diethylamide, to give the corresponding 3-substituted indoles is well established1,2 although very reactive halides, such as methyl iodide and benzyl chloride, occasionally give 1,3-disubstituted indoles3. We report now that indolylmagnesium iodide is alkylated by β-dimethylaminoethyl chloride to afford N,N-dimethyltryptamine4. The method appears to be general and, although the reaction conditions are critical, it provides a convenient direct synthesis of substituted tryptamines.

The indolylmagnesium iodide reagent was prepared in the usual manner2 from an indole and ethylmagnesium iodide in dry anisole at 10°C. The mixture was cooled to -5°C and a solution of 2-molar equivalents of β-dimethylaminoethyl chloride in dry benzene was added. After 8 hours at -5°C the mixture was allowed to warm slowly to room temperature, left overnight, and then added to aqueous ammonium chloride. The product was obtained via extraction into dilute hydrochloric acid and subsequent neutralisation.

Indole, 2-methylindole and 2-phenylindole afforded respectively, 25, 30 and 15% conversion into the corresponding dimethyltryptamines. These were identified by elemental analysis and comparison of infrared spectra and mp with authentic materials5,6. In each case the crude basic product was subjected to thin layer chromatography and no other substituted indoles were detected.

Alternative conditions were investigated for the reaction with 2-phenylindole. We found that, in anisole, a higher temperature decreased the yield (e.g., only 3% conversion at 40°C) and no alkylated products were obtained from reactions in tetrahydrofuran or in ether, either in the cold or upon heating.

The C-alkylation of indolylmagnesium iodide is particularly interesting in comparison with other metal indole derivatives. We found that 2-phenylindolyl sodium prepared from the indole and sodium hydride, did not react with β-dimethylaminoethyl chloride in anisole at -5°C, but at a higher temperature N-alkylation occurred7 and after 4 hours at 80°C 1-dimethylaminoethyl-2-phenylindole was obtained in 70% conversion. The latter, which has not previously been reported, was recrystallised from light petroleum to give needles having mp 64-66°C (hydrochloride, needles, mp 223-224.5°C). Similar results were obtained in tetrahydrofuran or dimethylformamide and in no case could the C-alkylated product be detected.

The lithium derivative of 2-phenylindole was prepared by exchange with butyl lithium in benzene, anisole was then added and most of the benzene was removed by distillation. The reaction with β-dimethylaminoethyl chloride for 4 hours at 84°C gave the N alkylated product in 23% conversion while at -5°C for 8 hours less than 1% conversion was effected. In neither case was there evidence of C-alkylation.

The contrast between N-alkylation of the indolylsodium and C-alkylation of the indolylmagnesium derivatives is interesting and the reduced nucleophilicity of the indolic nitrogen of the magnesyl compound indicates that the nitrogen is shielded from attack or is stabilised by co-ordination. If indolylmagnesium and indolylsodium are essentially similar ionic species, as has been suggested by Reinecke et al.8, our results imply that, at least in anisole, the indolylmagnesium complex is not dissociated. If the magnesium is associated with the indolic nitrogen then co-ordination of the solvent to magnesium could provide effective shielding and so prevent N-alkylation. Interpretation is complicated by the solvent effect whereby the reaction has been favoured by anisole, the less basic ether.

Further discussion of the mechanism is limited by the possibility that at least two alkylating species may be present. For instance there is good evidence9 to support the view that β-dimethylaminoethyl chloride, though formally an alkyl halide, usually reacts with nucleophiles via the dimethylethylene-immonium ion. The alkylation of indolylmagnesium at -5°C, but not at higher temperatures, certainly implies a competing reaction.
References
Hoshino, T. & Tamura, K., Ann. Chem 500, 42 (1933);
Wieland, H., Konz, W. & Mittasch, H., Ann. Chem. 513, 1 (1934);
Binder, H. & Wegler, R., Arch. Pharm., 275, 506 (1937);
Nametkin, S. S., Dzbanovskii, N. A. & Rudnev, A. G., Compt. Rend. Acad. Sci. U.S.S.R., 32, 333 (1941)
Majima, R. & Hoshino, T., Ber. 58B, 2042 (1925); Williamson, W. R. N., J. Chem. Soc. 2834 (1962)
e.g. Hoshino, T. Ann. Chem. 500, 35 (1933)
The preparation of tryptamine from indolylmagnesium bromide and ethylene imine has been reported by Bucourt, R. & Vignau, M., Bull. Soc. Chim. France 1190 (1961)
Hoshino, T. & Shimodaira, K., Ann. Chem. 520, 19 (1935)
Ames, A. F., Ames, D. E., Coyne, C. R., Grey, T. F., Lockhart, 1. M. & Ralph, R. S., J. Chem. Soc. 3388 (1959)
cf. Wright, J. B., J. Amer. Chem. Soc. 71, 1028 (1949)
Reinecke, M. G., Johnson, H. W. & Sebastian, J. F., Tetrahedron Letters 18, 1183 (1963)
Bartlett, P. D., Ross, S. D. & Swain, C. G., J. Amer. Chem. Soc., 71, 1415 (1949); Schultz, E. M. & Sprague, J. M., J. Amer. Chem. Soc., 70, 48 (1948) and references cited therein
NMR Study of Some Organometallic Indole Derivatives
J. Org. Chem. 36(21), 3091-95 (1971)Indolylmagnesium bromide
To 1.2 g of magnesium (99.99%), in 15 ml of dry THF, was slowly added 5.2 g of ethyl bromide in 10 ml of THF, without cooling but with vigorous stirring. After the reaction was completed 5.0 g of indole in 30 ml of dry THF was added. The liberated ethane was measured in an inverted graduated cylinder filled with water. The theoretical amount of ethane was collected in all cases. The indole Grignard reagent was completely soluble in THF.

Indolyllithium
Indolyllithium was prepared by adding 5.0 g of indole in 15 ml of THF to a refluxing mixture of 0.35 g of lithium hydride in 45 ml of THF. The resulting mixture was refluxed for 10-15 hr. The indolyllithium thus formed appeared to be quite soluble.

Indolylsodium
A solution of 5.0 g of indole in 20 ml of dry THF was added to a mixture of 1 g of sodium hydride in 40 ml of refluxing THF. The mixture was heated under reflux for another 30-60 min.