Another common but maybe old fashioned amide forming method is just DCC + HObt to give the active ester which then is reacted with your amine. There are also other active esters such as pentafluorophenyl esters, N-hydroxysuccinimide esters that do the same. A more recent method uses triphpsgene as a coupling reagent which is a very clean reaction. Raney Nickel is a pain to work with due to its flammability, that would be my last choice in reductive aminations.
Raney nickel is flammable only if it is allowed to dry before deactivation. Having run reductions and dethiations on a multi gram-molar scale with Raney nickel safety awareness is heightened significantly and, following due diligence, we never had problems.
Did the Still-Gennari on 5.5 mol scale with KHMDS in toluene and 18-C-6 at -20 to 0 degrees with 80% yield and a cis:trans ratio of 30:1. You can separate them which we did for reference purposes and because the trans would come through the rest of the synthesis. Nice reaction if not a bit expensive. Note KHMDS in toluene separates on standing to give 2 phases so shake the bottle very well. See 10.1021/op034133
So I know you mentioned rainey nickel and im curious here whats the difference between that and urishibara nickel. Arent they both finely divided nickel or is the big difference particle size and the way they are made? To add on as well Nile red did a recent synthesis of nordihydrocapsacin and he reduced vanillin oxime to vanillyl amine with pd/c but also didnt get the best yield either.
@@ThatChemistOld Actually there are several types of Raney nickel with various activities. See one of the earlier Cumulative Volumes of Organic Synthesis for the preparations.
Does reducing 5-nitro vanillin (4-Hydroxy-3-methoxy-5-nitrobenzaldehyde) with Tin (||) Chloride in water or EtOH yield some kind of aniline derivative ?
it should, but nitro reductions are really case-specific; if Sn(II) doesn't do the job, you can try Fe/HCl, NaSH, or Pd/C & H2. Many reducing conditions exist for nitroarenes
@@ThatChemistOld it will be a while before I go doing molten hydroxide electrolysis...for safety reasons.. guessing the borohydride is too reactive to expect to reduce boric to borate in an "ionic liquid" , and ......
If I just mixed sodium cyanide with sodium borohydride and little HCl, would that be equivalent to sodium cyanoborohydride? Or is the compound more covalent than ionic like say a titanate.., if so I'll just buy the borohydride
@@petevenuti7355 As always, check the literature. I wouldn't do it. I remember from years ago an old chemist, who worked a lot with HCN, telllng me that it was best to be smoking a cigarette as the almond flavor of HCN would be greatly enhanced, otherwise it could be a problem.
I enjoyed your discussion but it is far from being inclusive. One should look at the cumulative indices of Organic Synthesis and appropriate reviews in Organic Reactions, etc. and also, the current edition of LaRock's "Comprehensive Organic Transformations" for starters. The literature is replete with examples. By the way Eschweiler is pronounced "Eschwyler". My problem with using DDC with anything is the sensitization factor from which some chemists painfully suffer even on minimal exposure. What about catalytic transfer hydrogenation with formic acid, sodium formate, or ammonium formate? (see reviews) I've reduced imines this way. In a way you discussed this. For amide formation what about the acitivated imidazolide derivative or the N-hydroxysuccimide ester of the carboxylic acid? Classic peptide chemistry here. At one time, I had made N-acyl derivatives of proline in a one pot reaction sequence with acid chlorides by first first converting proline to the N,O -bis trimethylsilyl derivative with HMDS eliminating NH3 in the process, then treating that with an acid chloride and eliminating TMSCl at reflux , then finally cleaving the silyl ester. This sequence was used in the preparation of many grams of the Squibb drug captopril which was not otherwise available to us at the time.
When I saw the addition of aluminum amalgam I thought to myself "hmm, this one seems a bit unusual, why include it if you struggle to find references for it?" Then it hit me, that's how Walter White did his reduction of the imine in his p2p cook. And sure enough, when checking out the source.... you memer.
Another common but maybe old fashioned amide forming method is just DCC + HObt to give the active ester which then is reacted with your amine. There are also other active esters such as pentafluorophenyl esters, N-hydroxysuccinimide esters that do the same. A more recent method uses triphpsgene as a coupling reagent which is a very clean reaction. Raney Nickel is a pain to work with due to its flammability, that would be my last choice in reductive aminations.
Raney nickel is flammable only if it is allowed to dry before deactivation. Having run reductions and dethiations on a multi gram-molar scale with Raney nickel safety awareness is heightened significantly and, following due diligence, we never had problems.
@@jackhinkley6162 I have too the fun begins when you filter off the Raney Nickel, lol. Wouldn't try it on kilo scale
There’s another neat route to amines (Hofmann rearrangement) but it’s oxidative, not reductive.
Thanks
Did the Still-Gennari on 5.5 mol scale with KHMDS in toluene and 18-C-6 at -20 to 0 degrees with 80% yield and a cis:trans ratio of 30:1. You can separate them which we did for reference purposes and because the trans would come through the rest of the synthesis. Nice reaction if not a bit expensive. Note KHMDS in toluene separates on standing to give 2 phases so shake the bottle very well. See 10.1021/op034133
cool!
So I know you mentioned rainey nickel and im curious here whats the difference between that and urishibara nickel. Arent they both finely divided nickel or is the big difference particle size and the way they are made? To add on as well Nile red did a recent synthesis of nordihydrocapsacin and he reduced vanillin oxime to vanillyl amine with pd/c but also didnt get the best yield either.
Raney Nickel has aluminum in it, while urishibara nickel has zinc
@@ThatChemistOld Actually there are several types of Raney nickel with various activities. See one of the earlier Cumulative Volumes of Organic Synthesis for the preparations.
Does reducing 5-nitro vanillin (4-Hydroxy-3-methoxy-5-nitrobenzaldehyde) with Tin (||) Chloride in water or EtOH yield some kind of aniline derivative ?
it should, but nitro reductions are really case-specific; if Sn(II) doesn't do the job, you can try Fe/HCl, NaSH, or Pd/C & H2. Many reducing conditions exist for nitroarenes
@@ThatChemistOld in this case only Fe\HCl in ethanol or in acetic acid is good, i tried this one using the Pd on carbon and it did not well
Anyway to make the Borohydride from boric acid and potassium cyanide? And would potassium Borohydride work as well.
boric acid probably not - KBH4 should work fine, just typically sodium is used
@@ThatChemistOld it will be a while before I go doing molten hydroxide electrolysis...for safety reasons.. guessing the borohydride is too reactive to expect to reduce boric to borate in an "ionic liquid" , and ......
If I just mixed sodium cyanide with sodium borohydride and little HCl, would that be equivalent to sodium cyanoborohydride? Or is the compound more covalent than ionic like say a titanate.., if so I'll just buy the borohydride
@@ThatChemistOld what about fluoroborate? React boric acid & HF. Why not?
@@petevenuti7355 As always, check the literature. I wouldn't do it. I remember from years ago an old chemist, who worked a lot with HCN, telllng me that it was best to be smoking a cigarette as the almond flavor of HCN would be greatly enhanced, otherwise it could be a problem.
I enjoyed your discussion but it is far from being inclusive. One should look at the cumulative indices of Organic Synthesis and appropriate reviews in Organic Reactions, etc. and also, the current edition of LaRock's "Comprehensive Organic Transformations" for starters. The literature is replete with examples. By the way Eschweiler is pronounced "Eschwyler". My problem with using DDC with anything is the sensitization factor from which some chemists painfully suffer even on minimal exposure. What about catalytic transfer hydrogenation with formic acid, sodium formate, or ammonium formate? (see reviews) I've reduced imines this way. In a way you discussed this. For amide formation what about the acitivated imidazolide derivative or the N-hydroxysuccimide ester of the carboxylic acid? Classic peptide chemistry here. At one time, I had made N-acyl derivatives of proline in a one pot reaction sequence with acid chlorides by first first converting proline to the N,O -bis trimethylsilyl derivative with HMDS eliminating NH3 in the process, then treating that with an acid chloride and eliminating TMSCl at reflux , then finally cleaving the silyl ester. This sequence was used in the preparation of many grams of the Squibb drug captopril which was not otherwise available to us at the time.
When I saw the addition of aluminum amalgam I thought to myself "hmm, this one seems a bit unusual, why include it if you struggle to find references for it?" Then it hit me, that's how Walter White did his reduction of the imine in his p2p cook. And sure enough, when checking out the source.... you memer.
that was literally the only reference I could find on Reaxys