I have found several publications demonstrating the conversion of carbonyl to amide in “one pot”. First, the oxime is formed, then it is rearranged using various catalysts (ZnO, CuCl2, Cu(OAc)2...).
The advantage of this approach is that the amide can be obtained in just a few hours, and two steps can be combined in one (formation of the oxime and Beckmann rearrangement), avoiding work-ups each time, while avoiding the use of too many reagents. According to the literature, an excellent yield is obtained each time (>90%) and amide of good purity. Moreover, these procedures use either water as solvent, or neat condition. This avoids the use of large quantities of solvent, sometimes flammable and toxic, and facilitates waste management. The work-ups in these publications are simple and don't require complicated purification.
I don't trust the neat conditions protocols, as they are carried out on a 1 mmol scale, and require solids to be stirred, which in practice doesn't work on a gram scale (at least my attempts following the protocols of “Solvent-Free and One-Step Beckmann Rearrangement of Ketones and Aldehydes by Zinc Oxide” with ZnO, and ”An efficient copper (II)-catalyzed direct access to primary amides from aldehydes under neat conditions” with CuSo4 were unsuccessful).
The publication I found the most promising was “Copper(II) acetate-catalyzed one pot conversion of aldehydes into primary amides through a Beckmann-type rearrangement”. In this case, you simply extract the medium with an organic solvent to recover the amide, and then the Rm can be used up to ten times for other batches (after adding hydroxylamine) before having to change it.
However, I can't get the amide either (I've tried all the publications on benzaldehyde, not on helional).
The publication seems to mention that freeing the hydroxylamine freebase with a base from the hydroxylamine HCl salt doesn't work for the reaction, which seems strange to me. So I tried the reaction freeing the freebase from the hydroxylamine HCl using sodium acetate or sodium carbonate, and without freeing it (just putting the HCl salt in the water).
I got nothing by freeing the freebase.
Nevertheless, with the HCl salt of hydroxylamine, after 1.5 days of reaction, I obtained what seemed to me to be benzonitrile, as I was obtaining benzoic acid after acid hydrolysis of the compound obtained. So I guess you have to wait maybe even longer to complete the reaction. (and all the aromatic aldehydes also form the nitrile in parallel to the amide.)
I also think that the HCl salt of hydroxylamine converts Cu(OAc)2 to CuCl2, which is also used as a catalyst for Beckmann rearrangements.
So I thought I'd share the publications with you, in case any of you feel like giving it a try, and why not succeed in making MDA syntesis from helional much simpler and with better yields.
You can obtain the publications here : https://www.sci-hub.se (The site is banned in some countries, use a VPN or tor to access it)
- An efficient copper (II)-catalyzed direct access to primary amides from aldehydes under neat conditions
doi: http://dx.doi.org/10.1016/j.tetlet.2012.01.029
- Copper(II) acetate-catalyzed one-pot conversion of aldehydes into primary amides through a Beckmann-type rearrangement
doi: http://dx.doi.org/10.1016/j.tet.2012.03.085
- Ketones to amides via a formal Beckmann rearrangement in ‘one pot’: a solvent-free reaction promoted by anhydrous oxalic acid. Possible analogy with the Schmidt reaction
doi: http://dx.doi.org/10.1016/j.tetlet.2003.08.038
- Solvent-Free and One-Step Beckmann Rearrangement of Ketones and Aldehydes by Zinc Oxide
doi: https://doi.org/10.1055/s-2002-31964
Various catalysts are tested:
Cost efficient synthesis of amides from oximes with indium or zinc catalysts
doi: http://dx.doi.org/10.1016/j.tetlet.2010.03.048
Here is the procedure for the publication I found most promising:
4.2. General procedure for the synthesis of amides:
To a solution of copper(II) acetate (0.04 mmol) in water (1 mL) were added the corresponding aldehyde (3, 2 mmol) and the hydroxylamine (4, 2 mmol). After 2 days stirring at 110 C the mixture was quenched with a saturated solution of ammonium chloride (10 mL), or added ether (2 mL) for the recycling process. The mixture was extracted with AcOEt (310 mL) and washed with brine (10 mL), after drying with anhydrous MgSO4, the organic layer was filtered on Celite and the solvents were removed under low pressure (15e18 Torr). The product was purified recrystallization from chloroform/hexane mixtures to give the corresponding product 2. Amides 2a, 26 2b, 27 2c, 27 2d, 17 2e, 28 2f, 29 2g, 27 2h, 17 2j, 30 2k, 17 2l30 and 2m17 are commercially available and were characterized by comparison of their physical and spectroscopic data with those of pure examples. Yields are included in Table 4 (Fig. 1 for recycling processes). Physical and spectroscopic data, as well as literature data for known compounds, follow.
(doi: http://dx.doi.org/10.1016/j.tet.2012.03.085)
The advantage of this approach is that the amide can be obtained in just a few hours, and two steps can be combined in one (formation of the oxime and Beckmann rearrangement), avoiding work-ups each time, while avoiding the use of too many reagents. According to the literature, an excellent yield is obtained each time (>90%) and amide of good purity. Moreover, these procedures use either water as solvent, or neat condition. This avoids the use of large quantities of solvent, sometimes flammable and toxic, and facilitates waste management. The work-ups in these publications are simple and don't require complicated purification.
I don't trust the neat conditions protocols, as they are carried out on a 1 mmol scale, and require solids to be stirred, which in practice doesn't work on a gram scale (at least my attempts following the protocols of “Solvent-Free and One-Step Beckmann Rearrangement of Ketones and Aldehydes by Zinc Oxide” with ZnO, and ”An efficient copper (II)-catalyzed direct access to primary amides from aldehydes under neat conditions” with CuSo4 were unsuccessful).
The publication I found the most promising was “Copper(II) acetate-catalyzed one pot conversion of aldehydes into primary amides through a Beckmann-type rearrangement”. In this case, you simply extract the medium with an organic solvent to recover the amide, and then the Rm can be used up to ten times for other batches (after adding hydroxylamine) before having to change it.
However, I can't get the amide either (I've tried all the publications on benzaldehyde, not on helional).
The publication seems to mention that freeing the hydroxylamine freebase with a base from the hydroxylamine HCl salt doesn't work for the reaction, which seems strange to me. So I tried the reaction freeing the freebase from the hydroxylamine HCl using sodium acetate or sodium carbonate, and without freeing it (just putting the HCl salt in the water).
I got nothing by freeing the freebase.
Nevertheless, with the HCl salt of hydroxylamine, after 1.5 days of reaction, I obtained what seemed to me to be benzonitrile, as I was obtaining benzoic acid after acid hydrolysis of the compound obtained. So I guess you have to wait maybe even longer to complete the reaction. (and all the aromatic aldehydes also form the nitrile in parallel to the amide.)
I also think that the HCl salt of hydroxylamine converts Cu(OAc)2 to CuCl2, which is also used as a catalyst for Beckmann rearrangements.
So I thought I'd share the publications with you, in case any of you feel like giving it a try, and why not succeed in making MDA syntesis from helional much simpler and with better yields.
You can obtain the publications here : https://www.sci-hub.se (The site is banned in some countries, use a VPN or tor to access it)
- An efficient copper (II)-catalyzed direct access to primary amides from aldehydes under neat conditions
doi: http://dx.doi.org/10.1016/j.tetlet.2012.01.029
- Copper(II) acetate-catalyzed one-pot conversion of aldehydes into primary amides through a Beckmann-type rearrangement
doi: http://dx.doi.org/10.1016/j.tet.2012.03.085
- Ketones to amides via a formal Beckmann rearrangement in ‘one pot’: a solvent-free reaction promoted by anhydrous oxalic acid. Possible analogy with the Schmidt reaction
doi: http://dx.doi.org/10.1016/j.tetlet.2003.08.038
- Solvent-Free and One-Step Beckmann Rearrangement of Ketones and Aldehydes by Zinc Oxide
doi: https://doi.org/10.1055/s-2002-31964
Various catalysts are tested:
Cost efficient synthesis of amides from oximes with indium or zinc catalysts
doi: http://dx.doi.org/10.1016/j.tetlet.2010.03.048
Here is the procedure for the publication I found most promising:
4.2. General procedure for the synthesis of amides:
To a solution of copper(II) acetate (0.04 mmol) in water (1 mL) were added the corresponding aldehyde (3, 2 mmol) and the hydroxylamine (4, 2 mmol). After 2 days stirring at 110 C the mixture was quenched with a saturated solution of ammonium chloride (10 mL), or added ether (2 mL) for the recycling process. The mixture was extracted with AcOEt (310 mL) and washed with brine (10 mL), after drying with anhydrous MgSO4, the organic layer was filtered on Celite and the solvents were removed under low pressure (15e18 Torr). The product was purified recrystallization from chloroform/hexane mixtures to give the corresponding product 2. Amides 2a, 26 2b, 27 2c, 27 2d, 17 2e, 28 2f, 29 2g, 27 2h, 17 2j, 30 2k, 17 2l30 and 2m17 are commercially available and were characterized by comparison of their physical and spectroscopic data with those of pure examples. Yields are included in Table 4 (Fig. 1 for recycling processes). Physical and spectroscopic data, as well as literature data for known compounds, follow.
(doi: http://dx.doi.org/10.1016/j.tet.2012.03.085)
