AMT in the MW oven

[indole_amine]

This one isn't new at all; it is the reference from entry 5 in

this document

(https://www.thevespiary.org/rhodium/Rhodium/chemistry/it-290.html).

Interesting about it is the fact that they reduce the indolylnitroalkane to the amino derivative with the same reducing system they use for forming the pyrrole ring: nickel boride/hydrazine hydrate. Seems like a versatile reagent couple for the topic tryptamine chemistry in general, dare I say!

As starlight recently encountered problems while trying to reduce a similar indolyl-nitroalkane with Pd/C, this seemed like a good alternative to me: condense aldehyde and nitroethane, "saturate" the C=C bond using aequous NaBH₄, and then reduce the nitro group with Ni₂B/N2H4*H2O! Sounds like easy going, don't you think?

(the talked-about thread - another knoevenagel/henry approach to alpha-alkylated tryptamines:

Post 511247

(starlight: "The preparation of AET", Tryptamine Chemistry))


Nickel boride/hydrazine hydrate reduction of aromatic and aliphatic nitro compounds. Synthesis of 4-(benzyloxy)indole and .alpha.-alkyltryptamines
(David H. Lloyd, David E. Nichols)
J. Org. Chem. 1986; 51(22); 4294-4295

https://www.thevespiary.org/rhodium/Rhodium/hive/hiveboard/picproxie_docs/000448477-J_Org_Chem_1986_51_22_4294-4295.pdf" target="_blank" title="Download this file">

"(...)In a further investigation of the general utility of these reagents, we have discovered that similar reaction conditions also effect the reduction of aliphatic nitro compounds. Several substituted 1-(indol-3-yl)-2-nitroalkanes 4a-4c were reduced to the corresponding alpha-alkyltryptamines 5a-5c as illustrative examples. Indolylnitroalkanes were prepared by the condensation of substituted indoles 3a-3c with the appropriate nitroolefin, an extension of the method of Ranganathan(6). It appears that a variety of substituted alpha-alkyltryptamines may be readily prepared by this two-step method."
(they also describe the experimental details of the condensation reaction between indole and 2-nitropropene   )



and here's one of the references their article is based upon (referred to as "the method of Ranganathan"   ):

Nitroethylene: a stable, clean, and reactive agent for organic synthesis
(Darshan Ranganathan, C. Bhushan Rao, Subramania Ranganathan, Ashok K. Mehrotra, Radha Iyengar)

J. Org. Chem. 1980; 45(7); 1185-1189

(https://www.thevespiary.org/rhodium/Rhodium/pdf/nitroethene.in.organic.synthesis.pdf)



_{indole_amine}

[indole_amine]

"55ml of the methylamine acetate in IPA solution made above was put in a 250ml erlenmeyer flask with 14.4g (100mmol) Indole-3-carboxaldehyde and 9.9ml (110mmol) 1-Nitropropane. A condenser was attached to the flask and the stirred mixture was heated on a waterbath at 55-56C for 7 hours."
(

Post 514779

(starlight: "Satisfactory condensation method", Tryptamine Chemistry)


Now that looks like the imine pathway IMO. At least it would explain why he used an amine acetate rather than free amine/ammonia as catalyst (acid moiety needed). Other reasons?


_{indole_amine}

[starlight]

Hest: Why should alkylation of primary amines to yield tertiary amines be a bad idea? I have seen it being done many times already (although not with tryptamine)...(?)

The problem with trying to form dimethyl tryptamines through alkylation of tryptamine is the formation of quaternary salts (over-alkylation). If you use less alkylating reagent, I believe you just end up with a mixture of quaternary salt, starting substrate and maybe tiny amounts of mono-methylated or dimethylated product. The more the amine become alkylated, the more it is receptive to further alkylation (until it is the quaternary salt of course).

Here is a post with some links to further information:

Post 208020

(Lilienthal: "You can't dimethylate tryptamines with MeI or DMS", Tryptamine Chemistry)

Other alkylations with larger alkyl groups have been made to work though.

[indole_amine]

According to the same thread you referenced to, quaternary tryptammonium salts gotten from MeI alkylation can be reconverted to N,N-dimethyltryptamines with ethanolamine.

So: condense indolylaldehyde and nitromethane, reduce the nitrostyrene double bond with aequ. NaBH₄, then aminate via nickel borate/hydrazine, triacetoxyborohydride,cyanoborohydride or other selective reducing agent to get tryptamine (or do both at once with LiAlH₄), hope for not having touched the indole nitrogen   , and do whatever you like with it (there are many alkylhalides - and what about alpha-ethyl-(N,N-dimethyl)tryptamine btw? Think I gonna consult TiHKAL...) Nice if it would work.
(or, if you want N,N-DMT: simply alkylate with HCHO/NaBH₃CN - that is, unless Lilienthal is right with his cyclization theory about tetrahydro-betacarbolines...)

_{indole_amine}

[kjb1891]

Do you think that using 1-nitropropane instead of nitroethane in hest's MW method above would yield AET?

[Lilienthal]

Sure, it will.

[kjb1891]

How good do think the yeilds would be for AET compared to how good the yeilds were for AMT in the MW method?

[Rhodium]

Important:

The microwave procedure above does not produce AMT directly, but rather the nitroalkene precursor (3-Indolyl-2-nitropropene) which can be reduced to AMT using LiAlH₄ or any other known method.

[indole_amine]

And with 1-nitropropane, the intermediate/precursor substance is called 1-(indol-3-yl)-2-nitrobut-2-ene.

But the yield with 1-nitropropane will not be even half as high as when nitroethane is used in above condensation. Reason: 1-nitropropane is too long of a molecule, it can result in two different condensation products, and only one of these is the wanted one...

Oh, and there is a thread by Starlight out there, dealing with exactly this type of compound and exactly this type of reaction, too - I quoted the procedure whole seven posts earlier (

Post 533225

(indole_amine: "hmm", Tryptamine Chemistry)...

_{indole_amine}

[indole_amine]

[Maharajah]

I realize this may be a newbee question, but is Indole-3-carboxaldehyde a suitable substitution for Indole-3-aldehyde?  Thanks

[Barium]

It is the same thing, just different names.

[Maharajah]