[Rookie_OC_Lover]

in one step of a synthesis i found the following question popping up :

which way do you think is better to gain a better yield and milder reaction condition ?

Method 1 : Carboxylic acid to acetyl-chloride then making the amide then reduction to remove Oxygen.
Method 2 : Reduction then making acid chloride and then attaching the amine to make the amine group.

R is a chain of 5 carbons with no Oxygen containing groups.

TnX

[magician4]

hint:

my personal best guess you'll might share after looking up the problems of amine alkylation


regards

Ingo

[Rookie_OC_Lover]

my personal best guess you'll might share after looking up the problems of amine alkylation.

Problems of Amine alkylation ?
what kind of problems you mean ?

[magician4]

N-quarternization, elimination (at the alkyl) , elevated temperatures for sec. amines ...

those problems come into my mind


... and I don't see none of equal heftiness at route # 1


regards

Ingo

[Rookie_OC_Lover]

But I guess the problems you named may happen in both methods. or i'm wrong ?

in fact my question can be summarized to this :

reducing an amide is better (considering yields, reagents, conditions) or reducing the carboxylic acid ?

attaching R¹R²NH to a Acid chloride is more recommended or to the 1° chlorides ?

TnX

[magician4]

But I guess the problems you named may happen in both methods. or i'm wrong ?

I don't see that forming an amide form an acid chloride and a sec. amine does even come in the ballpark of the problems involved with amine alkylation: acylation and alkylation make a big difference !

Insofar, I don't see that this problem occurs on both pathways

... and the rest of the pathways seem comparable to me, hence don't make a big difference

regards

Ingo

[Rookie_OC_Lover]

I got now what you say Magician4.
but what do you think about reducing that amide ?
I neither can use LAH nor Red-Al.
based on my researches it's not easy to reduce amides as other groups.

do you have a suggestion to improve this step of my synth?
can you think of any alternative ways to build that final R-CH2-CH2-N(Et)2 ?

TnX

[magician4]

though there is a broader range of substances  which will transform acids to alcohols, the transformation amides  amines is by no way a miracle: LiAlH₄ will do the job nice and clean for you, and in high yields,  comparable to the reduction of acids with other substances


regards

Ingo

[camptzak]

what is the R group in this diethylamide synthesis?

[Rookie_OC_Lover]

what is the R group in this diethylamide synthesis?

5 carbons no other groups :

[Dan]

I neither can use LAH nor Red-Al.
based on my researches it's not easy to reduce amides as other groups.

Why can't you use LAH etc.?

Borane should do the job. There are other mild methods too - e.g. transition metal-ctalysed reduction with silanes or activation of the amide with Tf₂O before reduction.

[Rookie_OC_Lover]

Why can't you use LAH etc.?

can't buy or order it.
don't wanna get into legality matters. as I'm not doing this as a organization .etc.

in fact I was considering metal-catalyzed reductions.
one i found was using Hantzsch esters to do it. but i was thinking about replacing the Tf2O with something cheaper.
anything making a good leaving group for me would be great.

does anyone know how to carry out a metal-catalyzed reduction of amides without using Triflic stuff at all ?

Thanks a lot for support.

[Archer]

You could use the McFadyen-Stevens ester reduction from the ethyl ester (although I am not sure whether this works with aliphatic acids) or Rosenmund-Saitzew reduction  from the acid chloride to the aldehyde (hydrogenation over poisoned catalyst) then it would be simple reductive amination with diethylamine.

[Borek]

buying/using LAH or Diethlamine is NOT illegal. they are watched, to me, it means they make trouble.
synthesizing amines is NOT illegal.
reducing carboxylic acids, or amides is NOT illegal too.

We don't discuss drug synthesis here, and your approach doesn't make the discussion easier, as converting acid to diethylamine is a step in the synthesis of a well known drug. You failed to convince me you are trying to do something else.

Topic locked.