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All 9 posts Subject: Pseudo-"wet"- BH4 amination BH4 Please login to post Down

Bandil
(The Archetypical "Good Guy")
04-28-04 16:30
No 503533
      Pseudo-"wet"- BH4 amination BH4
(Rated as: excellent)

Hi!

Bariums wet reductive-amination, has gained great use throughout this forum. Although it gives nice yields - they are always lower than when using anhydrous conditions (mostly because some of the ketone is reduced to the alcohol), because the imine is formed in equilibrium with the ketone. Under anhydrous conditions the imine is in a rather "pure" state.

In order to push the limits on this reaction, i decided to turn to my old love - molecular sieves smile , and test the usefullness in this reaction.

para-fluoro-P2P was aminated with a 40% commercial aqueous methylamine solution in the following manner:

25 mmole pfP2P was dissolved in 30 mL's IPA (predried with MgSO₄). 40 mmole methylamine (3.1 g 40% aqueous solution) was put in the same beaker. Subsequently 15 g's¹ 3A molecular sieves was added, and the whole mess stirred for two hours at room temperature.

The sieves where filtered off² and rinsed with an additional small amount of dry IPA. The combined IPA/imine was put in a flask and stirred. 1 g NaBH₄³ was added in one portion, to this and stirred violently overnight at room temperature. The flask was covered with some foil during the night.

A control experiment was made with the exact same amounts, using the "normal" wet-amination scheme, in order to get some usefull results⁴. This was also reduced overnight.

The following day, both flasks where quenched with acetic acid (untill pH = 2). Totally 50 mL's of water was added to each. The IPA was stripped at atmospherical pressure. The water in the "dry" flask was completely clear after stripping, while the control flask was somewhat unclear with some yellowish oil remaining(probably pfP2Pol). The acidic water phases where washed with 2*20 mL's toluene. Basifying with NaOH caused a white oil to precipitate. This was extracted with 3*20 mL's DCM. The DCM phases where dried over epsom salt, and the solvent stripped.

Both the experiments gave a sligthly yellow tinted oil (GC-MS has not been conducted yet). The "dry" flask gave 3.4 g's of p-fluoro-methamphetamine, and the wet one gave 2.4 g's. This corresponds to a 81% and 58% yield. Thus using molecular sieves (which are dirt-cheap and reuseable, its possible to greatly improve the yields on this easy reaction.) The reaction is still "wet", meaning that the need for alcoholic methylamine has been eliminated. Methylamine generated in-situ from the hydrochloride and an alkali hydroxide can most likely be used just as easy.

I'd advice everyone to get some sieves - they truly rock.

Now ill go flush that evil N-methylated amphetamine down some drain - its probably evil wink

Regards
Bandil

Notes:
1:
Theoretically 12 g's should be used (20% absorbance) - just added a litte extra to be sure.

2:
To reuse them, they where rinsed with dilute HCl, and then pure water a few times. After a few hours in the oven, they are ready to go again.

3:
Way to much borohydride - half is more than enough. Was just to lazy to crush those tablets.

4:
I am rarely able to get the same yields as Barium, due to my somewhat more "sloppy" nature. Thus i ran a control experiment, to check things out. It was also done in order to get some usefull data - and not just another drug candidate wink

Nuke the whales!

Barium
(Heavyweight Chempion(eer))
04-28-04 16:37
No 503534
      What can I say

Two tumbs up Bandil! smile
It truly warms my heart to see my methods being used and improved.

XrLeap
(Hive Bee)
07-31-04 03:55
No 522852
      Methylamine generated in-situ from the ...

Methylamine generated in-situ from the hydrochloride and an alkali hydroxide can most likely be used just as easy.

hi Bandil:)

Can someone use the methylamine.hcl and NaOH solution as in Barium's wet amination(to generate methylamine gas in situ) and seperate them apart from the IPA(since they don't mix well), then stir with the mol sieves, then proceed to add NaBH4 with the usual workup?

Sorry about the long sentence and SWIM is not able to make his question short..... blush

oops i did it again

zero_nrg
(Newbee)
08-01-04 22:59
No 523141
      isopropyl and h20

Unless I´m mistaken, isopropyl alcohol is completely miscible with water. Also, assuming you could do what you suggest, why would you need the molecular sieves after the formation of the imine?
__________________________________________________________
Can someone use the methylamine.hcl and NaOH solution as in Barium's wet amination(to generate methylamine gas in situ) and seperate them apart from the IPA(since they don't mix well), then stir with the mol sieves, then proceed to add NaBH4 with the usual workup?
___________________________________________________________

Rhodium
(Chief Bee)
08-02-04 01:47
No 523158
User Picture       In their pure state they are miscible

Unless I´m mistaken, isopropyl alcohol is completely miscible with water.

In their pure state they are miscible, but water with dissolved salts is not fully miscible with IPA.

^{The Hive - Clandestine Chemists Without Borders}

XrLeap
(Hive Bee)
08-27-04 11:31
No 527768
      Hi Bandil, Thanks for taking time to answer my

Hi Bandil,

Thanks for taking time to answer my rather stupid questions blush .

SWIM would like to understand in this Pseudo-"wet"- BH4 amination BH4, why is it that the alkali hydroxide is not used to push the methylamine out from water to IPA? Was it because that methylamine.hcl was used in Barium's, 40% aq was used in this case?

Was it that the mol sieves(3A) has "sucked" away the H20 and the gas would just go into IPA?

Wouldn't the mol sieves also "suck" away the methylamine a bit?

Was the stirring of before filtering the mol sieves violent, just as violent as Barium's method?

Lastly, another stupid question which SWIM has posted in another thread. The NaBH4 was added as in solid form, not as solution? Can one use IPA as solvent and then add them into the main mixture?

Oops, so many questions, so little knowledge of SWIM's blush .

oops i did it again

armageddon
(Hive Bee)
08-29-04 19:30
No 528140
User Picture       Mol. sieves

Molecular sieves are able of absorbing molecules smaller than a certain diameter (with 3A sieves, this is 3 Angstrom), with 3A sieves being only able to absorb water and every molecule being smaller than water.

But methylamine is way bigger than water, when seen as a molecule. So the sieves take up water while leavingbehind the methylamine(g), which is instead taken up in the IPA.

Hence they are called "sieves"...

Greetz A

Pleased to meet you hope you get my name.
But whats puzzlin you is the nature of my game!

XrLeap
(Hive Bee)
09-10-04 18:43
No 530672
      SWIM attempted this Pseudo-"wet"-...

SWIM attempted this Pseudo-"wet"- BH4 amination BH4 with MDP2P, faced a serious problem. The NaBH4 wouldn't dissolve in the dry IPA......

SWIM tried to just dissolve NaBH4 in IPA, it was not able to dissolve even 0.5g in 50ml(under room temperature). Pls help as how this can be done, with what temperature?

oops i did it again

armageddon
(Hive Bee)
09-10-04 19:46
No 530686
User Picture       I guess if you're using fairly dry IPA, you...

I guess if you're using fairly dry IPA, you could expect the NaBH4 to not dissolve at once - therefore Bandil suggested to dump it in all at once and let react overnight...

(I would at least guess that the reason for the slow rxn he mentions is exactly this low solubility - right?)

greetz

Hehehe....

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	All 9 posts		Subject: Pseudo-"wet"- BH4 amination BH4		Please login to post		Down


		Bandil (The Archetypical "Good Guy") 04-28-04 16:30 No 503533				Pseudo-"wet"- BH4 amination BH4 (Rated as: excellent)
						Hi! Bariums wet reductive-amination, has gained great use throughout this forum. Although it gives nice yields - they are always lower than when using anhydrous conditions (mostly because some of the ketone is reduced to the alcohol), because the imine is formed in equilibrium with the ketone. Under anhydrous conditions the imine is in a rather "pure" state. In order to push the limits on this reaction, i decided to turn to my old love - molecular sieves , and test the usefullness in this reaction. para-fluoro-P2P was aminated with a 40% commercial aqueous methylamine solution in the following manner: 25 mmole pfP2P was dissolved in 30 mL's IPA (predried with MgSO₄). 40 mmole methylamine (3.1 g 40% aqueous solution) was put in the same beaker. Subsequently 15 g's¹ 3A molecular sieves was added, and the whole mess stirred for two hours at room temperature. The sieves where filtered off² and rinsed with an additional small amount of dry IPA. The combined IPA/imine was put in a flask and stirred. 1 g NaBH₄³ was added in one portion, to this and stirred violently overnight at room temperature. The flask was covered with some foil during the night. A control experiment was made with the exact same amounts, using the "normal" wet-amination scheme, in order to get some usefull results⁴. This was also reduced overnight. The following day, both flasks where quenched with acetic acid (untill pH = 2). Totally 50 mL's of water was added to each. The IPA was stripped at atmospherical pressure. The water in the "dry" flask was completely clear after stripping, while the control flask was somewhat unclear with some yellowish oil remaining(probably pfP2Pol). The acidic water phases where washed with 220 mL's toluene. Basifying with NaOH caused a white oil to precipitate. This was extracted with 320 mL's DCM. The DCM phases where dried over epsom salt, and the solvent stripped. Both the experiments gave a sligthly yellow tinted oil (GC-MS has not been conducted yet). The "dry" flask gave 3.4 g's of p-fluoro-methamphetamine, and the wet one gave 2.4 g's. This corresponds to a 81% and 58% yield. Thus using molecular sieves (which are dirt-cheap and reuseable, its possible to greatly improve the yields on this easy reaction.) The reaction is still "wet", meaning that the need for alcoholic methylamine has been eliminated. Methylamine generated in-situ from the hydrochloride and an alkali hydroxide can most likely be used just as easy. I'd advice everyone to get some sieves - they truly rock. Now ill go flush that evil N-methylated amphetamine down some drain - its probably evil Regards Bandil Notes: 1: Theoretically 12 g's should be used (20% absorbance) - just added a litte extra to be sure. 2: To reuse them, they where rinsed with dilute HCl, and then pure water a few times. After a few hours in the oven, they are ready to go again. 3: Way to much borohydride - half is more than enough. Was just to lazy to crush those tablets. 4: I am rarely able to get the same yields as Barium, due to my somewhat more "sloppy" nature. Thus i ran a control experiment, to check things out. It was also done in order to get some usefull data - and not just another drug candidate Nuke the whales!



		Barium (Heavyweight Chempion(eer)) 04-28-04 16:37 No 503534				What can I say
						Two tumbs up Bandil! It truly warms my heart to see my methods being used and improved.



		XrLeap (Hive Bee) 07-31-04 03:55 No 522852				Methylamine generated in-situ from the ...
						Methylamine generated in-situ from the hydrochloride and an alkali hydroxide can most likely be used just as easy. hi Bandil:) Can someone use the methylamine.hcl and NaOH solution as in Barium's wet amination(to generate methylamine gas in situ) and seperate them apart from the IPA(since they don't mix well), then stir with the mol sieves, then proceed to add NaBH4 with the usual workup? Sorry about the long sentence and SWIM is not able to make his question short..... oops i did it again



		zero_nrg (Newbee) 08-01-04 22:59 No 523141				isopropyl and h20
						Unless I´m mistaken, isopropyl alcohol is completely miscible with water. Also, assuming you could do what you suggest, why would you need the molecular sieves after the formation of the imine? __________________________________________________________ Can someone use the methylamine.hcl and NaOH solution as in Barium's wet amination(to generate methylamine gas in situ) and seperate them apart from the IPA(since they don't mix well), then stir with the mol sieves, then proceed to add NaBH4 with the usual workup? ___________________________________________________________



		Rhodium (Chief Bee) 08-02-04 01:47 No 523158				In their pure state they are miscible
						Unless I´m mistaken, isopropyl alcohol is completely miscible with water. In their pure state they are miscible, but water with dissolved salts is not fully miscible with IPA. ^{The Hive - Clandestine Chemists Without Borders}



		XrLeap (Hive Bee) 08-27-04 11:31 No 527768				Hi Bandil, Thanks for taking time to answer my
						Hi Bandil, Thanks for taking time to answer my rather stupid questions. SWIM would like to understand in this Pseudo-"wet"- BH4 amination BH4, why is it that the alkali hydroxide is not used to push the methylamine out from water to IPA? Was it because that methylamine.hcl was used in Barium's, 40% aq was used in this case? Was it that the mol sieves(3A) has "sucked" away the H20 and the gas would just go into IPA? Wouldn't the mol sieves also "suck" away the methylamine a bit? Was the stirring of before filtering the mol sieves violent, just as violent as Barium's method? Lastly, another stupid question which SWIM has posted in another thread. The NaBH4 was added as in solid form, not as solution? Can one use IPA as solvent and then add them into the main mixture? Oops, so many questions, so little knowledge of SWIM's. oops i did it again



		armageddon (Hive Bee) 08-29-04 19:30 No 528140				Mol. sieves
						Molecular sieves are able of absorbing molecules smaller than a certain diameter (with 3A sieves, this is 3 Angstrom), with 3A sieves being only able to absorb water and every molecule being smaller than water. But methylamine is way bigger than water, when seen as a molecule. So the sieves take up water while leavingbehind the methylamine(g), which is instead taken up in the IPA. Hence they are called "sieves"... Greetz A Pleased to meet you hope you get my name. But whats puzzlin you is the nature of my game!



		XrLeap (Hive Bee) 09-10-04 18:43 No 530672				SWIM attempted this Pseudo-"wet"-...
						SWIM attempted this Pseudo-"wet"- BH4 amination BH4 with MDP2P, faced a serious problem. The NaBH4 wouldn't dissolve in the dry IPA...... SWIM tried to just dissolve NaBH4 in IPA, it was not able to dissolve even 0.5g in 50ml(under room temperature). Pls help as how this can be done, with what temperature? oops i did it again



		armageddon (Hive Bee) 09-10-04 19:46 No 530686				I guess if you're using fairly dry IPA, you...
						I guess if you're using fairly dry IPA, you could expect the NaBH4 to not dissolve at once - therefore Bandil suggested to dump it in all at once and let react overnight... (I would at least guess that the reason for the slow rxn he mentions is exactly this low solubility - right?) greetz Hehehe....

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