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All 8 posts Subject: propenylbenzene to amphetamines via isocyanates Please login to post Down

ning
(acetaminophanatic)
04-04-04 07:02
No 498965
      propenylbenzene to amphetamines via isocyanates

Got to thinking of this one recently. Found a thread Post 258096 (Rhodium: "Safrole to MDMA via isocyanates?", Serious Chemistry) where Rhodium had the same idea, but to make a methylamine.

My spin is this: To take bromosafrole, or other propenylbenzene, and react it with sodium cyanate, yielding an isocyanate, which can either bee reduced to the N-methyl version, or hydrolyzed to the plain primary amine. This would neatly solve the annoying overalkylation problem that limits the yield of the basic bromosafrole bomb process.

My thinking was that this might be worth considering again, seeing as how it now seems that NaOCN has been rendered OTC by extensive hive research Post 442105 (DRIVEN: "NaOCN from urea and sodium carbonate", Methods Discourse) for making 4-MAR.

Polverone's post Post 445115 (Polverone: "More cyanate info", Methods Discourse) on cyanates and Bandil's post Post 354295 (Bandil: "trans-4-MAR synth w/o cyanogenbromide writeup!", Methods Discourse) suggest that cyanates might persist long enough in aqueous solution to make use of phase-transfer catalysis techniques. Perhaps if the aqueous phase is buffered with something noncompetitive like sodium acetate. Otherwise, just stirring NaOCN with haloalkane might do the trick. (eventually)

In other words, NaOCN might bee an excellent "OTC" replacement for NaN3 in haloalkane-->amine syntheses, and perhaps would even bee better, because it would bee both more flexible, and require less steps.

Anybee tried this before or have refs?

Catching a buzz @ the Hive

Vitus_Verdegast
(Hive Addict)
04-04-04 11:26
No 498985
User Picture       alkyl halide + KOCN

Found this:

Reactant : potassium isocyanate, i-propyl halide
Product : isocyano-acetic acid isopropyl ester

Yield : 92 percent
Solvent : dimethylformamide
Time : 3 hour(s)
Temperature : 55 - 60 °C

Suzuki, Mamoru et al; Chem. Pharm. Bull. EN, 28, 8, (1980) 2374-2383

"It is the declared policy of the US Government to create a Drug-Free America by 1995."

ning
(acetaminophanatic)
04-04-04 20:36
No 499045
      Looks good, if it's what I think it is...

But that terminology has me a little confused.
Isocyanoacetic acid ... ester?
In the case of isocyanic acid, that actually means R-NCO, I guess. But what's the acetic part?

In my mind I'm seeing this:

Me2CH.X + KOCN --> Me2CHNCO + KX

Since that's reaction I'd expect. Is this correct?
If so, hey, that's not bad at all!

Thanks, Vitus!

EDIT:

Wait a minute! isocyanoacetic acid isopropyl ester is this:

CN.CH2.COO.CH(Me)2

How does that come from KOCN and Me2CHX ?

Catching a buzz @ the Hive

Vitus_Verdegast
(Hive Addict)
04-04-04 23:13
No 499080
User Picture       Aaaargh!! stupid brain!

Sorry to give you false hope, ning, I posted that when I was still half-asleep this morning crazy

It's actually potassium isocyanate aka potassium isocyanoacetate (CNCH2COOK) not cyanate... crazy crazy frown

sorry mate! I guess I should refrain from posting before I have my coffee. mad

A new search generated the following, I also included acyl halides as the substrate:

Prashad, Mahavir; Tomesch, John C.; Houlihan, William
Synthesis 6 (1990) 477-480

Abstract
Selective Monocarbamoylation of Symmetrical Diols with Alkyl Halides and Potassium Cyanate Using Phase-Transfer Catalysis

A convenient method for the selective monocarbamoylation of diols by reaction with alkyl isocyanates, generated in situ from alkyl halides and potassium cyanate under phase-transfer catalysis, is described. Under these conditions the ease of reaction shows the following order cis-diols > trans-diols and diols > monoalcohols.An increase in the number of methylene groups between two hydroxyl groups lead to a decrease in product yields.A plausible mechanism to explain these results is proposed.

Deng, M. Z.; Caubere, P.; Senet, J. P.; Lecolier, S.
Tetrahedron Volume 44, number 19 (1988) 6079-6086

Abstract
CONDENSATION OF ACYL CHLORIDE ON SODIUM CYANATE : PREPARATION OF ACYL ISOCYANATES

The catalytic effects of various metal halides and solvents on the reaction of benzoyl chloride with sodium cyanate were studied.It has been found that SnCl4, and ZnCl2 catalyze the reaction to give the corresponding acyl isocyanates in good yields.The scope of the reaction was studied and a number of aroyl isocyanates and their derivatives were prepared.A few non aromatic isocyanates and their derivatives were also prepared.

Reactants: 4-phenoxy-benzoyl chloride ; sodium cyanate
Product: 4-phenoxy-benzoyl isocyanate
Yield: 76 percent (BRN=5022396)
Catalyst: SnCl4
Solvent: 1,2-dichloro-benzene
Time: 2 hour(s)
Other Conditions: Heating

Reactants: propionyl chloride ; sodium cyanate
Product: propionyl isocyanate
Yield: 52 percent
Catalyst: SnCl4
Solvent: 1,2-dichloro-benzene
Time: 8 hour(s)
Temperature: 80°C

Reactants: 3-chloro-benzoyl chloride ; sodium cyanate
Product: 3-chloro-benzoyl isocyanate
Yield: 81 percent
Catalyst: SnCl4
Solvent: 1,2-dichloro-benzene
Time: 2 hour(s)
Other Conditions: Heating

Reactants: 2-chloro-benzoyl chloride ; sodium cyanate
Product: o-chlorobenzoyl isocyanate
Yield: 80 percent
Catalyst: SnCl4
Solvent: 1,2-dichloro-benzene
Time: 2 hour(s)
Other Conditions: Heating

Reactants: 3-methoxy-benzoyl chloride ; sodium cyanate
Product: 3-methoxy-benzoyl isocyanate
Yield: 78 percent
Catalyst: SnCl4
Solvent: 1,2-dichloro-benzene
Time: 2 hour(s)
Other Conditions: Heating

Reactants: sodium cyanate ; benzoyl chloride
Product: benzoyl isocyanate
Yield: 83 percent
Catalyst: SnCl4
Solvent: 1,2-dichloro-benzene
Time: 2 hour(s)
Other Conditions: Heating

Reactants: 4-methyl-benzoyl chloride ; sodium cyanate
Product: 4-methyl-benzoyl isocyanate
Yield: 81 percent
Catalyst: SnCl4
Solvent: 1,2-dichloro-benzene
Time: 2 hour(s)
Other Conditions: Heating

Reactants: 2-ethyl-2-bromo-butyryl bromide ; mercury (I)-cyanate
Product: 2-ethyl-2-bromo-butyryl isocyanate

Patent DE271682

Reactants: sodium cyanate ; (3-bromo-propoxy)-benzene
Product: (3-isocyanato-propoxy)-benzene
Solvent: dimethylformamide
Time: 1 hour(s)
Other Conditions: Heating

"It is the declared policy of the US Government to create a Drug-Free America by 1995."

ning
(acetaminophanatic)
04-05-04 06:07
No 499136
      For Rhodium:
(Rated as: good read)

Reduction of isocyanates w/ LiAlH4: JOC 1953?, 1338 by Finholt, Anderson, & Agre

They reduce several isocyanates.

isocyanate : yield
Phenyl 86%
1-Naphthyl 90%
Ethyl    78%

isothiocyanate: yield
Phenyl 96%
Allyl    81%

They use slightly more than equimolar amounts of LiAlH4 to reduce. The equation for reduction is suggested to be:

4 RNCO + 3 LiAlH4 --> LiAl[RNCH3]4 + 2 LiAlO2

With post-reaction hydrolysis yielding the free methylamines.

Experimental details:

The isocyanates were dissolved in 5x their weight of ether and dripped carefully into an ethereal solution of LiAlH4, then refluxed for 1.5 to 2 hours. The excess hydride was destroyed with water and 100-200 ml 30% NaOH solution was added and the whole shebang refluxed. It seems the LiAl salt was rather persistant and hard to hydrolyze.

Would MDMA survive being refluxed in 30% lye? Hmmm...that could be a problem.

Catching a buzz @ the Hive

ning
(acetaminophanatic)
04-08-04 09:09
No 499691
      Isocyanate nucleophilicity

Turns out (JACS 1960, 1778) that OCN- ion is about as good of a nucleophile as NO2- (nitrite) or F- (fluoride). Which is to say (apparently) not too good, but not too bad either.

Hey, how about using this to make nitroethane? If cyanate is about as reactive as nitrite, EtCl or EtBr + NaOCN --> EtNCO --> EtN, then use hydrogen peroxide/urea or a homemade ozone generator to make the lovely nitroethane. Probably much less annoying than trying to homemake NaNO2, and all completely OTC. Yield --> ?, but at least there won't be the annoying yield-sucking competing side reaction like the nitrite alkylation method has...

Catching a buzz @ the Hive

Rhodium
(Chief Bee)
04-08-04 12:31
No 499717
User Picture       TOXIC!

Probably much less annoying than trying to homemake NaNO2

I would strongly advise against making any short-chain isocyanates like ethyl isocyanate, as they are very volatile and highly toxic. EtNCO has a bp of 60°C and an LD₅₀ of only 56mg/kg!

It was a gas leakage from a tank of Methyl Isocyanate which caused the death of nearly 4000 citizens and injury of a further 2500 in the 1984 Bhopal incident in India.

^{The Hive - Clandestine Chemists Without Borders}

ning
(acetaminophanatic)
04-08-04 17:19
No 499736
      True

but if it was reacted in situ? I was thinking to bubble ethyl chloride gas through an alkaline aqueous solution of NaOCN in H2O/isopropanol. Supposedly the rate of hydrolysis of cyanate ion is much slower in alkaline solution. I wonder if it'd be slow enough?

(heh heh bedroom bhopal)

Catching a buzz @ the Hive

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	All 8 posts		Subject: propenylbenzene to amphetamines via isocyanates		Please login to post		Down


		ning (acetaminophanatic) 04-04-04 07:02 No 498965				propenylbenzene to amphetamines via isocyanates
						Got to thinking of this one recently. Found a thread Post 258096 (Rhodium: "Safrole to MDMA via isocyanates?", Serious Chemistry) where Rhodium had the same idea, but to make a methylamine. My spin is this: To take bromosafrole, or other propenylbenzene, and react it with sodium cyanate, yielding an isocyanate, which can either bee reduced to the N-methyl version, or hydrolyzed to the plain primary amine. This would neatly solve the annoying overalkylation problem that limits the yield of the basic bromosafrole bomb process. My thinking was that this might be worth considering again, seeing as how it now seems that NaOCN has been rendered OTC by extensive hive research Post 442105 (DRIVEN: "NaOCN from urea and sodium carbonate", Methods Discourse) for making 4-MAR. Polverone's post Post 445115 (Polverone: "More cyanate info", Methods Discourse) on cyanates and Bandil's post Post 354295 (Bandil: "trans-4-MAR synth w/o cyanogenbromide writeup!", Methods Discourse) suggest that cyanates might persist long enough in aqueous solution to make use of phase-transfer catalysis techniques. Perhaps if the aqueous phase is buffered with something noncompetitive like sodium acetate. Otherwise, just stirring NaOCN with haloalkane might do the trick. (eventually) In other words, NaOCN might bee an excellent "OTC" replacement for NaN3 in haloalkane-->amine syntheses, and perhaps would even bee better, because it would bee both more flexible, and require less steps. Anybee tried this before or have refs? Catching a buzz @ the Hive



		Vitus_Verdegast (Hive Addict) 04-04-04 11:26 No 498985				alkyl halide + KOCN
						Found this: Reactant : potassium isocyanate, i-propyl halide Product : isocyano-acetic acid isopropyl ester Yield : 92 percent Solvent : dimethylformamide Time : 3 hour(s) Temperature : 55 - 60 °C Suzuki, Mamoru et al; Chem. Pharm. Bull. EN, 28, 8, (1980) 2374-2383 "It is the declared policy of the US Government to create a Drug-Free America by 1995."



		ning (acetaminophanatic) 04-04-04 20:36 No 499045				Looks good, if it's what I think it is...
						But that terminology has me a little confused. Isocyanoacetic acid ... ester? In the case of isocyanic acid, that actually means R-NCO, I guess. But what's the acetic part? In my mind I'm seeing this: Me2CH.X + KOCN --> Me2CHNCO + KX Since that's reaction I'd expect. Is this correct? If so, hey, that's not bad at all! Thanks, Vitus! EDIT: Wait a minute! isocyanoacetic acid isopropyl ester is this: CN.CH2.COO.CH(Me)2 How does that come from KOCN and Me2CHX ? Catching a buzz @ the Hive



		Vitus_Verdegast (Hive Addict) 04-04-04 23:13 No 499080				Aaaargh!! stupid brain!
						Sorry to give you false hope, ning, I posted that when I was still half-asleep this morning It's actually potassium isocyanate aka potassium isocyanoacetate (CNCH2COOK) not cyanate... sorry mate! I guess I should refrain from posting before I have my coffee. A new search generated the following, I also included acyl halides as the substrate: Prashad, Mahavir; Tomesch, John C.; Houlihan, William Synthesis 6 (1990) 477-480 Abstract Selective Monocarbamoylation of Symmetrical Diols with Alkyl Halides and Potassium Cyanate Using Phase-Transfer Catalysis A convenient method for the selective monocarbamoylation of diols by reaction with alkyl isocyanates, generated in situ from alkyl halides and potassium cyanate under phase-transfer catalysis, is described. Under these conditions the ease of reaction shows the following order cis-diols > trans-diols and diols > monoalcohols.An increase in the number of methylene groups between two hydroxyl groups lead to a decrease in product yields.A plausible mechanism to explain these results is proposed. Deng, M. Z.; Caubere, P.; Senet, J. P.; Lecolier, S. Tetrahedron Volume 44, number 19 (1988) 6079-6086 Abstract CONDENSATION OF ACYL CHLORIDE ON SODIUM CYANATE : PREPARATION OF ACYL ISOCYANATES The catalytic effects of various metal halides and solvents on the reaction of benzoyl chloride with sodium cyanate were studied.It has been found that SnCl4, and ZnCl2 catalyze the reaction to give the corresponding acyl isocyanates in good yields.The scope of the reaction was studied and a number of aroyl isocyanates and their derivatives were prepared.A few non aromatic isocyanates and their derivatives were also prepared. Reactants: 4-phenoxy-benzoyl chloride ; sodium cyanate Product: 4-phenoxy-benzoyl isocyanate Yield: 76 percent (BRN=5022396) Catalyst: SnCl4 Solvent: 1,2-dichloro-benzene Time: 2 hour(s) Other Conditions: Heating Reactants: propionyl chloride ; sodium cyanate Product: propionyl isocyanate Yield: 52 percent Catalyst: SnCl4 Solvent: 1,2-dichloro-benzene Time: 8 hour(s) Temperature: 80°C Reactants: 3-chloro-benzoyl chloride ; sodium cyanate Product: 3-chloro-benzoyl isocyanate Yield: 81 percent Catalyst: SnCl4 Solvent: 1,2-dichloro-benzene Time: 2 hour(s) Other Conditions: Heating Reactants: 2-chloro-benzoyl chloride ; sodium cyanate Product: o-chlorobenzoyl isocyanate Yield: 80 percent Catalyst: SnCl4 Solvent: 1,2-dichloro-benzene Time: 2 hour(s) Other Conditions: Heating Reactants: 3-methoxy-benzoyl chloride ; sodium cyanate Product: 3-methoxy-benzoyl isocyanate Yield: 78 percent Catalyst: SnCl4 Solvent: 1,2-dichloro-benzene Time: 2 hour(s) Other Conditions: Heating Reactants: sodium cyanate ; benzoyl chloride Product: benzoyl isocyanate Yield: 83 percent Catalyst: SnCl4 Solvent: 1,2-dichloro-benzene Time: 2 hour(s) Other Conditions: Heating Reactants: 4-methyl-benzoyl chloride ; sodium cyanate Product: 4-methyl-benzoyl isocyanate Yield: 81 percent Catalyst: SnCl4 Solvent: 1,2-dichloro-benzene Time: 2 hour(s) Other Conditions: Heating Reactants: 2-ethyl-2-bromo-butyryl bromide ; mercury (I)-cyanate Product: 2-ethyl-2-bromo-butyryl isocyanate Patent DE271682 Reactants: sodium cyanate ; (3-bromo-propoxy)-benzene Product: (3-isocyanato-propoxy)-benzene Solvent: dimethylformamide Time: 1 hour(s) Other Conditions: Heating "It is the declared policy of the US Government to create a Drug-Free America by 1995."



		ning (acetaminophanatic) 04-05-04 06:07 No 499136				For Rhodium: (Rated as: good read)
						Reduction of isocyanates w/ LiAlH4: JOC 1953?, 1338 by Finholt, Anderson, & Agre They reduce several isocyanates. isocyanate : yield Phenyl 86% 1-Naphthyl 90% Ethyl 78% isothiocyanate: yield Phenyl 96% Allyl 81% They use slightly more than equimolar amounts of LiAlH4 to reduce. The equation for reduction is suggested to be: 4 RNCO + 3 LiAlH4 --> LiAl[RNCH3]4 + 2 LiAlO2 With post-reaction hydrolysis yielding the free methylamines. Experimental details: The isocyanates were dissolved in 5x their weight of ether and dripped carefully into an ethereal solution of LiAlH4, then refluxed for 1.5 to 2 hours. The excess hydride was destroyed with water and 100-200 ml 30% NaOH solution was added and the whole shebang refluxed. It seems the LiAl salt was rather persistant and hard to hydrolyze. Would MDMA survive being refluxed in 30% lye? Hmmm...that could be a problem. Catching a buzz @ the Hive



		ning (acetaminophanatic) 04-08-04 09:09 No 499691				Isocyanate nucleophilicity
						Turns out (JACS 1960, 1778) that OCN- ion is about as good of a nucleophile as NO2- (nitrite) or F- (fluoride). Which is to say (apparently) not too good, but not too bad either. Hey, how about using this to make nitroethane? If cyanate is about as reactive as nitrite, EtCl or EtBr + NaOCN --> EtNCO --> EtN, then use hydrogen peroxide/urea or a homemade ozone generator to make the lovely nitroethane. Probably much less annoying than trying to homemake NaNO2, and all completely OTC. Yield --> ?, but at least there won't be the annoying yield-sucking competing side reaction like the nitrite alkylation method has... Catching a buzz @ the Hive



		Rhodium (Chief Bee) 04-08-04 12:31 No 499717				TOXIC!
						Probably much less annoying than trying to homemake NaNO2 I would strongly advise against making any short-chain isocyanates like ethyl isocyanate, as they are very volatile and highly toxic. EtNCO has a bp of 60°C and an LD₅₀ of only 56mg/kg! It was a gas leakage from a tank of Methyl Isocyanate which caused the death of nearly 4000 citizens and injury of a further 2500 in the 1984 Bhopal incident in India. ^{The Hive - Clandestine Chemists Without Borders}



		ning (acetaminophanatic) 04-08-04 17:19 No 499736				True
						but if it was reacted in situ? I was thinking to bubble ethyl chloride gas through an alkaline aqueous solution of NaOCN in H2O/isopropanol. Supposedly the rate of hydrolysis of cyanate ion is much slower in alkaline solution. I wonder if it'd be slow enough? (heh heh bedroom bhopal) Catching a buzz @ the Hive

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