Investigations into the mechanism of lactamization of lactones yielding in a novel route to biologically active tryptamine derivatives

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Tetrahedron, 2004, 60, 4567-4578
DOI:

10.1016/j.tet.2004.03.073

Michael Decker, Thi Thanh Huyen Nguyen and Jochen Lehmann

Abstract
The mechanism of lactamization of corresponding lactones was investigated by means of gas chromatography and synthesis of possible intermediates as references. Lactones react with amines via the amino acid with subsequent elimination of water to the corresponding lactams. In the first step, also hydroxyamides are in equilibrium with the lactones and amines, respectively, which are not able to form the amide though. This mechanism opens a new approach for the synthesis of N b-disubstituted tryptamines.

Keywords
Lactamization; Lactones; Amino acids; Hydroxyamides; Tryptamines; Hallocinogens.

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Scheme 6. Formation of N[beta]-disubstituted tryptamines (17) from 4,9-dihydropyrano[3,4-b]indol-1(3H)-ones (2) and secondary amines.

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Several new tryptamines were synthesized, including some which are able to displace the 5-HT₂ antagonist ketanserin from the receptor. According to the pharmacological data these substances might bee potential hallucinogens but from the data it is not clear wether these compounds are agonists or antagonists on the 5-HT_2a receptor.
The authors also present a novel route to DET.

That's interesting. Now we only need to see how hard it is to synthesize the tricyclic starting material 2:

The 4,9-dihydropyrano[3,4-b]indol-1(3H)-ones (2) necessary for the following reactions can be either obtained out of ?-valerolactone by reaction with oxalyl ester, followed by reaction with diazotized aniline (Japp–Klingemann-reaction),¹³ or out of ?-butyrolactone and oxalyl esters, respectively, following hydrolysis and reaction with phenylhydrazones, as described previously.¹⁴

13. Lehmann, et. al, Arch. Pharm. Pharm. Med. Chem. 1987, 320, 1202–1209.
14. Lehmann, et. al, Arch. Pharm. Pharm. Med. Chem. 1987, 320, 698–704.

gentle Friedel-crafts alkylation of the hydrolyzed product of a Reissert synthesis with ethylene chlorohydrin, followed by dehydration.

i.e 2-nitrotoluene --[reissert synthesis]-->
ethyl indole-2-methanoate --[F.C. Alkylation]-->
ethyl 3-hydroxyethyl indole-2-methanoate --[gentle hydrolysis or heating??]-->
cyclized lactone intermediate.

Then lactamize with the alkylamine of choice and decarboxylate. Nice!

Molecule:

alkylate ("OC(=O)c1nc2ccccc2c1.ClCCOH>>OC(=O)c1nc2ccccc2c1CCO")

Molecule:

dehydrate ("OC(=O)c1nc2ccccc2c1CCO>>O3C(=O)c1nc2ccccc2c1CC3")


 Mmm, mmm good.

Then again, would the presence of that methanoic acid group screw up the alkylation procedure?

Then again, would the presence of that methanoic acid group screw up the alkylation procedure?

Catastrophically. Carboxylic acids are more active than alkyl chlorides in FC a(c/lk)ylations.

then what?

EDIT:

Seems like the presence of an acid ester in the 2-position isn't going to change the alkylation pattern, at least how I  draw the resonance structures. That's good.

EDIT2:

Post 268709

(flipper: "reissert indole synt", Tryptamine Chemistry) mentions

http://www.orgsyn.org/orgsyn/prep.asp?prep=cv5p0567

(ETHYL INDOLE-2-CARBOXYLATE), which says at the bottom:

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The acid or its ester serves as a readily accessible indole capable of electrophilic substitution at the 3-position

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(H. Fischer and K. Pistor, Ber., 56B, 2213 (1923), R. H. Cornforth and R. Robinson, J. Chem. Soc., 680 (1942))

So there you have it.