Dope Amine
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One-pot arylation/acylation of primary amines
Here's my thought: Use a phenylboronic acid and Cu2O to arylate a primary amine in methanol (Chan-Lam coupling). I *believe* the
byproduct of this reaction would be boric acid but I can't confirm this for sure anywhere. Assuming I am correct about the boric acid, one could then
filter the Cu2O and evaporate off the methanol leaving the product and boric acid. Then add toluene and the desired carboxylic acid for
acylation. This reaction is done at reflux with a dean-stark trap to drive off the water. An example can be found here: http://www.orgsyn.org/demo.aspx?prep=v81p0262 Ok, so maybe having to evaporate the methanol and then adding toluene isn't technically one-pot but
it could avoid a work-up. 
Otherwise, does anyone have a good method of acylating a primary amine with a carboxylic acid? Chan-Lam coupling can be done on amides so the
arylation could be done after the acylation instead. Maybe someone can think of a good one-pot from doing it in that order?
Boron rocks!
[Edited on 15-4-2014 by Dope Amine]
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Nicodem
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Quote: Originally posted by Dope Amine  | | Here's my thought: Use a phenylboronic acid and Cu2O to arylate a primary amine in methanol (Chan-Lam coupling). I *believe* the
byproduct of this reaction would be boric acid but I can't confirm this for sure anywhere. Assuming I am correct about the boric acid, one could then
filter the Cu2O and evaporate off the methanol leaving the product and boric acid. |
Yes, it is boric acid, though in methanol it can be in equilibrium with its esters. Some boric acid can therefore be lost during the filtration and
rotavaping, but you only need about 5 mol% of boric acid for most amidations (provided it works at all - not all acid/amine pairs are suitable for
boric acid amidations).
| Quote: | | Ok, so maybe having to evaporate the methanol and then adding toluene isn't technically one-pot but it could avoid a work-up. |
In the industry we call such operations telescoping synthesis or a telescoped reaction. This is where the product is not isolated, or where impurities
are only partially removed by some operation, and a crude product in a mixture or solution is used in the further step. The most common example is
where only an aqueous wash of the reaction mixture is applied and then the organic phase is used directly in the next step (or following a solvent
exchange).
This is in contrast to the one-pot reactions where the next reaction is performed without taking the mixture out of the "pot" and without any work-up
operations.
Of course, every chemist and every research group uses their own definitions and the terms telescoped and one-pot reactions are interchangeable to
some.
| Quote: | | Otherwise, does anyone have a good method of acylating a primary amine with a carboxylic acid? Chan-Lam coupling can be done on amides so the
arylation could be done after the acylation instead. Maybe someone can think of a good one-pot from doing it in that order? |
Developing one-pot reactions is intermediate to process development. For this reason you should first evaluate each chemical step separately to see
the conversions and check the impurity profiles. In some cases it is immediately obvious that the two steps could be combined in a one-pot reaction,
but sometimes it is just as immediately obvious this would be counter-productive. Some lazy chemists (I tend to be one such) like to try one-pots on
the fly, by just some cursory theoretical/literature evaluation. Sometimes this saves time, but if it does not work it can waste much more time. I
can't say that such a lazy-chemist strategy is actually time saving on a longer run.
It may appear that way, but it does not always. I have plenty of experience with boron and boronic acid catalysed amidations and can tell you that
they are extremely sensitive to the nature of the amine and the acid used. Generally, they work best for primary aliphatic amines and not so well for
the secondary or aromatic amines. They also tend not to work well (or not at all) for aromatic carboxylic acids. Sterically hindered caboxylic acids
(multiply alpha substitited) also do not work best.
The reactions that are too slow in toluene reflux usually tend to work more or less suitably in refluxing xylene, but the ones that do not give any
conversion at all in toluene usually don't work in xylene either.
You want to amidate a secondary aromatic amine. I would not bet on it working well. I hope you at least want to use an aliphatic non-bulky carboxylic
acid.
One of the best (non-expensive coupling reagents using) methods for amidations (of aromatic amines as well) in my experience is to use CDI. Though
even CDI fails at times, particularly on some heteroaryl acids. Another excellent method is to use alkyl chloroformates to form a mixed anhydride
(this one always never fails, but has a bit more chemoselectivity issues).
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
Read the The ScienceMadness Guidelines!
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Dope Amine
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Thanks so much Nicoderm for your thoughtful responses.
The drive behind this mental excursion was a synthetic attempt which appears to have gone awry (although it may be completely unrelated to the methods
discussed above):
4-amino-1-benzylpiperidine in methanol was reacted with 2-fluorophenylboronic acid.
-Although not specifically demonstrated in literature, it was assumed that the 2-fluoro group would not cause a significant reduction in yield of the
arylamine based on the results of high yields for the reaction of 4-fluorophenylboronic acid with aniline (was done in Et3N but this was probably
unnecessary), and the reactions of 4-fluoro, 4-bromo, and 2-bromophenylboronic acids with imidazole (no base present).
The secondary arylamine product was acylated with methoxyacetyl chloride.* The amide product was then N-debenzylated (the piperidine nitrogen) with
Pd/C and ammonium formate (CTH) and then N-alkylated with either an alpha or beta bromo alkane to yield (hopefully) the two desired final products.**
*The synthesis of methoxyacetyl chloride was attempted by the simple distillation of methoxyacetic acid and benzoyl chloride. Unfortunately a vigreux
column was not available so proper separation of the desired product was a concern (a shortpath with a column would seem to be ideal). The distillate
did not begin to come over until the flask temperature was near 112 deg. C. (b.p. of methoxyacetyl chloride) BUT the vapor of the distillate was found
to be 50-60 deg. C. which was VERY concerning because the boiling point of acetyl chloride is 52 deg. C. It is known that the distillate would come
over at a lower temperature because it being carried over with HCl gas but this difference in boiling point seems very extreme. Does it seem probable
that a rearrangement is occurring at or near the boiling point of methoxyacetyl chloride which is causing the undesired production of acetyl
chloride??? This appears to be a major concern to at least one chemist. Anyway, the acid chloride distillate was distilled a second time, again not
climbing out of the distilling flask until the bath temp was >112 but the vapor again was near the boiling point of acetyl chloride! After
completion of the distillation upon cleaning of the distilling flask the smell of benzoic acid was noted which means that benzoyl chloride was carried
over into the receiving flask during the first distillation. Benzoyl chloride would be expected to cause the distillation vapor temperature to be
higher which makes the vapor temperature of 50-60 even more concerning. In the past, the preparation of propionyl chloride by a similar method
starting with propionic acid was done without any concerns but the vapor temperature was not noted at that time. Again, the temperature of the vapor
was likely lower than the boiling point of propionyl chloride but I doubt it was 50-60 degrees lower like in this recent case.
**The alkylation of the piperidine ring by alkyl halide was done in refluxing MIBK. There was concern afterwards that water might've caused problems
in this reaction because the MIBK was technical grade. Without NMR, who knows... 
Please Nicoderm, enlighten me with your insights!
BTW, I agree that the amidation of a secondary aromatic amine would probably be low-yielding. Similarly, the arylation of the secondary amide (if
the order were reversed) would probably have a yield approaching 30% at best so it seems best to stick with the route I have already layed out. Just
need to work out the kinks!
[Edited on 2-5-2014 by Dope Amine]
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Dr.Bob
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| Quote: Originally posted by Nicodem | | One of the best (non-expensive coupling reagents using) methods for amidations (of aromatic amines as well) in my experience is to use CDI.
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Are you referring to carbonyldiimidazole or the carbodiimides? Both work well for certain amidations, and I see them both called CDI, although I
normally use CDI for carbonyldiimidazole and either EDC or DCC for the carbodiimides. Both CDI and EDC can be very easy to work up, I always liked
EDC or its resin bound versions best as they could be worked up so easily, often by filtration or a very short silica gel column. Both are also
fairly readily available, compared to many other reagents, and lower priced, might even be on Ebay.
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