Author Topic: bromosafrole to MDMA via N-methyl carbamates  (Read 1493 times)

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ning

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bromosafrole to MDMA via N-methyl carbamates
« on: April 27, 2004, 04:51:00 PM »
Once upon a time, Drone342 had an idea to react bromosafrole with sodium methylamide, thereby eliminating overalkylation and raising yields. Only problem was, it is very difficult to deprotonate methylamine.

One day, ning was working on such a route and thought about what protecting groups could bee used to lower the pKa of the amine to low values. And shazam--there they were.

When an amine is Boc-ed or otherwise converted into a carbamate, its pKa drops to around 15, which is, in fact, very near that of NaOH. This means it now becomes very easy to deprotonate, and monoalkylate.

Now, we could use NaOH, or NaOMe, but that would probably hydrolyze our carbamate, which is bad. So ning suggests using PTC conditions, with bromosafrole, N-methyl carbamate, and Na2CO3 as dry base. Na2CO3 will not hydrolyze things like NaOH will. Ning can almost guarantee this will work and give high yield of monoalkylated amines.

Finally, the last problem. Where to obtain N-methyl carbamates? There are 2 ways, both of which aren't so hard.

First, if you are doing eleusis's hoffmann rearrangement of acetamide to methylamine, just do it in alcohol instead of water. It will form ethyl N-methyl carbamate, via the isocyanate intermediate of the hoffmann rearrangement.

Otherwise, for the truly lazy or adventurous, you can buy N-methyl 2-naphthyl carbamate off the shelf. It's an insecticide called Carbaryl, AKA Sevin. The highest concentration ning has seen it in is 22.5% solution.
There are many other "carbamate" poisons with other functions, herbacides, fungicides, etc., so there's lots of room to play...

This might bee also an interesting source of methylamine.




MeNH- + PhCH2CH(CH3).Br --> PhCH2CH(CH3).NHMe + Br- {very difficult!}
(N-)(Me)COOR + PhCH2CH(CH3).Br --> PhCH2CH(CH3).N(Me)COOR + Br- {much easier!}

PhCH2CH(CH3)N(Me)COOR + H2O + [OH-] --> PhCH2CH(CH3)NMe + ROH + CO2


SpicyBrown

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I'm not actually sure if you need to worry...
« Reply #1 on: April 28, 2004, 01:14:00 AM »
I'm not actually sure if you need to worry about hydrolyzing the carbamate with a base such as NaOH.  Both Boc and Cbz carbamates are stable to NaOH and in fact even NaH (at least for Cbz)  I recently read a paper where a unit was attached to a synthetic amino acid by an Sn2 reaction- The unit was N-(2-Cl-Cbz)-methoxylamine (not sure if the name is totally correct there; 2-Cl-Cbz is simply the Cbz protecting group with a chlorine on the ring).  It was deprotonated at the nitrogen with NaH and then reacted with the amino acid displacing a bromine on its side chain.

Other carbamates are base sensitive, like Fmoc, but that's due to the nature of the fluorenylmethyl group as opposed to the carbamate AFAIK.

I'm not in a position to find the ref just this minute, but if anybody's interested I can post it later.

And anyway now that you mention it, I think this seems like a potentially worthwhile route to MDMA from bromosafrole..

-SpicyBrown

ning

  • Guest
Carbamate sensitivity
« Reply #2 on: April 28, 2004, 04:37:00 AM »
Not sure either, but what I've heard is that Boc is much, much stronger against hydrolysis than simple alkyl carbamates (which is why it is used...). Also, NaH wouldn't hydrolyze anything, since it's a "dry" base. But NaOH, well, it forms water (HOH) when it takes a proton, so I guess it's particularly good at hydrolyzing things like that. Also, even in PTC, the ion extracted from the aqueous phase carries a small ball of water with it (from 3 to 6 H2O, typically). Apparently, carbonate ion, as a dibasic ion is really difficult to extract from the water phase (I guess because it would require two PTC molecules), so somehow use of carbonate avoids hydrolysis problems. It's a little weaker than hydroxide ion, but that's not a problem in this system because the carbamate is so easy to deprotonate. (On a more practical note, I think carbonate is cheaper than hydroxide anyway)

Ultimately, testing would resolve this issue. Is anhydrous system required or what?

Ease of hydrolysis is convenient for other reasons, though. We have to remove that protecting group later.  :)
Ideally it could bee done in one pot. After the reaction is complete, the system is diluted with water and stirred for a while. Then, an A/B extraction can be done to remove the formed amine.

Here's something interesting:

JOC 1979, 3391

On page 3394, they do this:













Molecule:

carbamates? ("c1cc(OC)c(OC)cc1C(=O)CCCl.CNC(=O)OC>>c1cc(OC)c(OC)cc1C(=O)CCN(C)C(=O)OC")



"The requisite [beta]-(N-methyl-N-carbomethoxy) ketone was easily prepared in 74% yield by the reaction of the known [beta]-chloro ketone with methyl N-methylcarbamate in the presence of a catalytinc amount of p-toluenesulfonic acid. [Monatsh. Chem., 102, 233 (1971)]"

"A mixture containing methyl N-methylcarbamate (11.3 g, 0.12 mol), 3,4-dimethoxy-3'-chloropropiophenone (14.4 g, 0.06 mol), and a catalytic amount of p-toluenesulfonic acid (ca. 50 mg) in toluene (250 ml) was heated at reflux for about 48 h. The mixture was then washed with saturated brine (1 x 100 mL) and dried (MgSO4), and the excess solvents were removed under reduced pressure. The crude ketourethane thus obtained was then recrystallized from ether-hexane to give 12.9 g (74%) as a white crystalline solid."

How does that work? Note the high yield, protection of aryl ether functions, and small excess of carbamate. Nice. Obviously ning doesn't understand carbamate chem well enough yet.

Ning suspects, at least for the moment, ordering this type of thing from chem supply will not bee suspicious.

Drug chemists usually don't use amino-acid protection functions in their evil syntheses. Hmm.....


Nicodem

  • Guest
Eliminating the elimination
« Reply #3 on: April 28, 2004, 11:23:00 AM »
Are we 100% sure that the problem with alkylation of 'bromosafrole' is only its low electrophylicity and thus a lausy reactivity. What are the side products of such alkylation? Maybe it is the HBr elimination side reaction that lowers the yields. This would form isosafrole as a side product. I don't truly believe in this being a problem but it might bee something to consider, especialy when alkylating with considerably basic nucleophyles like (carb)amides and at higher temperatures.


Rhodium

  • Guest
Suggested reading on bromosafrole rxn
« Reply #4 on: April 28, 2004, 11:29:00 AM »
Suggested reading:

Post 502454

(Rhodium: "Analysis of 'Bromosafrole Route' Preparations", Serious Chemistry)



ning

  • Guest
as far as I understand it
« Reply #5 on: April 28, 2004, 04:51:00 PM »
AFAIK, the main problems are:

Relatively low reactivity of bromosafrole,
Methylamine base has a low boiling point so you need a bomb,
Overalkylation of formed MDMA amine, forcing use of 10x methylamine or so to get a decent yield.

Look at those papers! 5g safrole gets 40 ml 40% methylamine! What excess would that be?

I guess elimination could be a problem. Dunno.

Rhodium, do you think adding hydroquinone or something to safrole when it's recieving HBr would raise yields by preventing anti-markovnikov free-radical pathways?


Rhodium

  • Guest
Anti-Anti-Markovnikov Additive
« Reply #6 on: April 28, 2004, 06:41:00 PM »
A radical inhibitor would be a good idea, but I cannot say if HQ would be the one best suited for the job or not.


ning

  • Guest
pKa of N-Methylcarbamates
« Reply #7 on: May 10, 2004, 07:22:00 AM »

http://www.chem.ucla.edu/research/org/MERLIC_GROUP/c_links/Amines_Amides.html



At the bottom, you will see a cyclic carbamate. It is rated to have a pKa of 12 under aqueous conditions.

The pKa calculator (

http://ibmlc2.chem.uga.edu/sparc/index.cfm

) calculates it to be 13.something.

This is an encouragement, because the calculator thinks N-methyl carbamate should have a pKa of 13.

It stands to reason that they would bee in the same order of magnitude. This means that the carbamate will bee almost fully deprotonated by NaOH, and within trivial reach of any PTC system.

How delightful!

I think it's worth a try.

BTW, heads up: Lots of hofmann rearrangement papers and refs coming in, showing how to make the aforementioned N-methyl carbamate in one step from acetamide.

Let's rock this town!


ning

  • Guest
Load 1
« Reply #8 on: June 16, 2004, 08:35:00 PM »
First, we'll start with the mother paper:

"New Strategies for the Hofmann Reaction", J. Chem. Tech. Biotech. 59; 1994, 271

In this paper they discuss many things, including formation of the aforementioned carbamates by performing the Hofmann rearrangement in alcohol. Yields were all above 90% from amides. This will be dealt with later. For the moment, I would direct attention to page 274, the section labeled "N-Alkylation of carbamates".



In the presence of a base, R1.NHCOO.R2 can undergo elimination of OR2 to give isocyanates or N-alkylation. Hence, N-alkylation of carbamates is favored when OR2 is a poor leaving group, eg R2 = Me. The reactivity of a simple carbamate is more akin to amides than to esters and hence forcing conditions are required for these reactions. N-Monosubstituted or unsubstituted carbamates are potential nucleophiles themselves. However, they are (by analogy with amides) poor nucleophiles and only act as such when converted to anions or when the nitrogen of the carbamate is adjacent to the reactive center (neighboring group participation).
   The success of this alkylation methyl-N-alkyl carbamates mainly depends on the efficient formation of the anion from corresponding carbamates, its extraction into the organic phase and subsequent reaction with alkylating agent, i.e. dimethyl sulfate (DMS).
   This was achieved by employing tetrabutyl ammonium hydrogen sulfate (TBA.HSO4) as PTC, powdered NaOH and K2CO3 as the base, and toluene as the reaction medium.
   The choice of base was arrived at after employing various bases generally used in the PTC reaction. Aqueous NaOH (50%) furnished only 8% of the product. The yield was drastically increased to 75% when powdered NaOH was used, further increasing to 95% with the addition of anhydrous K2CO3. Anhydrous K2CO3 may be acting not only as a base, but also as a dehydrating agent preventing the solvation of the carbamate anion and thus facilitating the alkylation.
....
general procedure for N-alkylation of carbamates:

A mixture of carbamate (0.05 mol), toluene (100 ml), powdered NaOH (0.2 mol), anhydrous K2CO3 (0.05 mol), and PTC (0.0025 mol) was stirred at room temp for 1 h. During stirring, a gelatinous mass was formed. DMS (0.06 mol) was added to the stirred mass at 30-35 C over a period of 30 min. The course of the reaction was monitored with TLC. The reaction mixture was stirred for 4 h to obtain a clear solution. Inorganics were filtered off and washed with toluene (2 x 20 ml). The combined filtrate and washings were washed with HCl (2 N, 3 x 50 ml), water (2 x 50 ml), and dried over anhydrous Na2SO4. Concentration of the solvent yielded the products.




What does this tell us? That PTC alkylation of carbamates is possible and high-yielding.

Next up, PTC alkylation of tBOC-protected guanidines. Why is this special? Because they use secondary alkyl bromides, just like our system of interest.

"Synthesis of Highly Functionalized Guanidines" JOC 2003, 2300



...Herein, we describe a relatively mild and efficient protocol for the guanidinylation of various alkyl halides in a biphasic medium containing an aqueous solution of PTC. This procedure is scaleable to muligrap quantities, yielding highly functionalyized and protected guanidines that are readily purified.
[...]
The N,N-bis-Boc-guanidine was regioselectively alkylated at one of the carbamate nitrogens. Alkylation of this substrate under phase-transfer conditions provides an alternative method for the synthesis of monosubstituted guanidines from alkyl bromides under milder conditions than previously reported. Furthermore, alkylation occurs only once even in the presence of a large excess of allyl bromide (5 equiv), with extended reaction times (24 h) or with heating (50 C). Other N1,N2-bis-Boc-N3,N3-disubstituted guanidines were allylated in high yield. The reaction is tolerant to a wide range of functional groups on the guanidine including esters, amines, ketones, alcohols, and alkenes. Competitive hydrolysis of the ethyl ester in 3e was minimized by reducing reaction time. [...] The procedure is readily adapted to larger scales, as exemplified by the allylation of tetrahydroisoquinoline-derived guanidine 3g, which was conducted on a 12 g (31.2 mmol) scale.[...]

Having demonstrated functional group tolerance in the guanidine component, the effect of variation of the electrophilic component was required. Specifically, guanidinylation of a range of electrophiles using the bis-Boc-protected model substrates 3a was examined. Saturated alkyl halides such as iodomethane and bromopropane were cleanly displaced by the guanidine nucleophile, although in the latter case, the reaction need to be heated to 50 C for 12 h. Secondary alkyl bromides could also be guanidinylated regioselectively to provide the isopropyl and cyclohexenyl guanidines in moderate yield. In contrast, secondary alkyl bromides underwent elimination using the NaH/DMF methodology, rather than alklation.
[...]
Since non-chlorinated solvents, such as toluene, are preferred industrially, the use of toluene as a cosolvent in the biphasic protocol was examined. Heating of guanidine substrate 3a with benzyl chloride in a biphasic mixture of toluene and water at 50 C for 10 h in the presence of the PTC and KOH gave the benzylated product 5r in 89% yield. The scope of the guanidinylation procedure was also extended to the use of mesylates, which are readily accessible from the corresponding alcohols. Clean alkylation of the guanidine was observed with propargyl bromide and 4-bromo-2-methyl-2-butene. Reaction at the secondary carbon of 3-bromocyclohexene, as with 2-bromopropane, was slower than the displacement at a primary carbon, and consequently, longer reaction times were required.
[...]
Other phase-transfer catalysts, such as tetrabutyl ammonium bromide and tetrabutyl ammonium chloride afforded products in yields similar to those obtained with tetrabutyl ammonium iodide.
[...]
Conclusion: An efficient method for the alkylation of N-dicarbamate-protected guanidines using a variety of alkyl halides has been established. Under this procedure, the acidic N-carbamate hydrogen is deprotonated using biphasic conditions, with a catalytic amount of tetrabutyl ammonium salt, as the phase-transfer catalyst, and then subsequently alkylated to yield highly functionalized guanidines from those currently utilized. In addition, the need for stoichiometric amounts of costly or highly reactive coupling reagents is circumvented. An attractive feature of this methodology is that few byproducts are generated and at the end of the reaction, simple aqueous workup followed by filteration through a short plug of silica gel (to remove the PTC) gives high yields of the desired products. Replacement of DCM with toluene as the organic solvent gives comparable results and is ideal for larger-scale preparation of substituted guanidines.

[...]

General procedure for PTC synthesis of guanidines
A biphasic solution of guanidine 3 (0.5 mmol), TBAI (0.05 mmol, 18 mg), and KOH (1 mmol, 56 mg) in a 1:1 mixture of DCM/H2O (5 mL) was treated with the alkyl halide or alkyl mesylate (0.6-1.0 mmol, depending on the electrophile) for 2-4 h, and then the reaction mixture was poured through H2O (25 mL) and extracted with DCM (3 x 10 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The product was purified by flash chromatography through a short column of silica gel.

General procedure for deprotection of guanidines
A solution of the guanidine (0.25 mmol) in 1 M aq HCl (2 mL) was stirred at room temperature for 4 h or until all of the starting material was consumed, as monitored by TLC. The reaction was concentrated in vacuo and purified by silica gel chromatography to give the unprotected guanidine as an HCl salt.



Boc-NH-C(-NR)=N-Boc + R-X ---> Boc-N(R)-C(-NR)=N-Boc

#   R-X              Time(h) Temp    Yield
----------------------------------------------------
1   Me.I               5      25      95 *
2   Pr.I              12      50      77 *
3   Pr.Br             12      50      81 *
4   Pr.Cl             48      50       0 *
5   iPr.Br            48      50      60
*
6   Bn.Br              4      25      95
7   Bn.Cl             12      25      88
8   Bn.OMs            16      25      92
9   HCC-CH2.Br         4      25      92
10  Me(Me)C=CHCH2.Br   4      25      99
11  3-Br cyclohexene  25      25      78
*
12  Bn=CH-CH2.Br       4      25      95
13  PhCO-CH2.Br        4      25      82

* = 2.2 equiv used, otherwise 1.2 equiv used





This is promising, because although the yields are not as high as they could be, this shows that carbamates can be PTC-alkylated with secondary bromides. Nice. Also note that they used the halide in excess and measured yield based on carbamate consumed, whereas we will be doing exactly the opposite, and probably use 2x excess carbamate.


More on the way.