(Member)
04-19-00 05:22
No 122771
(Rated as: excellent)
Author Topic: Synthetic challenge: Pseudo 2C-B
Rhodium
Administrator posted 11-24-98 02:09 PM
----------------------------------------
I was doing some thinking today, and the above synthetic target really gets me. The compound cannot be impossible to synthesize, but it sure seems like it. I cannot for my life devise a synthetic strategy for the compound which doesn't involve something like a dozen steps. Everything just places itself in the wrong positions.
Exercise: Devise a synthesis of 2,6-dimethoxy-4-bromo-phenethylamine using no speciality chemicals as starting materials.
Methylate the whole big mess, then separate via fractional distillation. An alternative non-OTC method would be to deprotonate 1,3-dimethoxybenzene with LiPh, then formylate it with formylalanine. This gives decent yields, but requires working with the very pyrophoric material I like to call "phenyllithium". (Praeparative Organische Chemie,Tl.II Following this disgusting binge of chemical consumption, knoevenhagel its ass with a little nitromethane (I don't think you'll need ref's for that.) Reduce it (again, use your imagination, 'cuz I'm lazy and you have the answer anyways), then finally brominate it with NBS. (Bromination: Aust.J.Chem. 44, 5, 1991, 705-728; JOC 50, 7, 1985, 1087-1105 Admittedly this is pretty crappy, but this was just my first response. What would really help would be a decent OTC formylation, but we'll see. -drone #342 -drone #342 P.S. I was the frist response; do I get a prise or what? Take care, Rhenium My email is stephanie_x@hotmail.com Thanks, Rhenium One interesting examply of getting an iodine in that position on a similar chemical that I'm sure would work is -drone #342 B) Starting from p-nitrotoluene, which is cheap. I'm not very comfortable with the conversion of (I) to (II), but I'm sure this works: (I) ---> 2,6-di-Br-4-NH2-toluene (VI) More steps, but all pretty high-yielding. C) Starting from m-nitrobenzaldehyde 3-NO2-benzaldehyde ---> 3-Br-5-NO2-benzaldehyde (I) Hey, some of you chem students, ask your professor what he thinks! But I was hoping somebody could eliminate such uncomfortable steps as lithiation, or reduction of an aromatic nitro in the prescense of a benzaldehyde. The rolte is still not as cheap or easy as the one for 2C-B itself I do like that Sandmeyer reduction; if you can manage to overcome the fact that nitro's are deactivating (I know there are conditions accomidating this, but I can't remember them.) For that matter, halides have a sort of dual activating/deactivating nature about them as well. -drone #342 1) nitration of phenethylamine with HNO3 and H2SO4 Chem.Ber.; 45; 1912; 2431; 2)bromination using FeBr2 Justus Liebigs Ann. Chem.; 231; 1885; 178; Tetrahedron; EN; 45; 17; 1989; 5565-5578; 4)Formation of a diazonium complex, follwed by the Sandmeyer reduction to convert the nitro into a bromo substituent in a one-pot-shot (more on this method later.) That's it! That's all there is to it! 4 Steps! Now that's good chemistry! I guess I may have been to hasty when I said it'll never be as easy as its 2,5-counterpart. I underestimated myself. Okay, maybe the last step constitutes 5 steps, but they're easy steps to do! -drone #342 [1] Larock, Comprehensive Organic Transformations; VCH: New York, 1989, 340 [2] Angew. Chem. 1960, 72, 294-315, 297 [3] J. Chem. Soc. Chem. Commun. 1983, 108 [4] J. Chem. Soc. Chem. Commun. 1987, 1409 [5] J. Org. Chem. 1987, 52, 691 Lilienthal, Why acetoxy? What's your angle? Do you have a means of readily turning a nitro into a acetoxy group, or a whole new plan in mind? -drone #342 Lilienthal, Why acetoxy? What's your angle? Do you have a means of readily turning a nitro into a acetoxy group, or a whole new plan in mind? -drone #342 That covers all the "biggies", so to speak, but I suppose the ethoxy analogs could be investigated, as other configurations of the same substitutents in the same 2,4,6-positions. All we need is a third-world country to look the other way, and we have a research project that could keep several bees going for years with oodles of meaningful research! -drone #342 -drone #342 JOC 53; 12; 1988; 2858-2859. In this paper, they use thionyl chloride and cook the daylights out of the compound (170 deg C). Yields look good, too. -drone #342 HBr, NaNO2/Cu Org. Syn. Coll. Vol. 1, 125 (1941)
drone 342
Member posted 11-24-98 08:28 PM
----------------------------------------
Hm, formylation of resourcinol, forming 40% 2,4-dihydroxybenzaldehyde and 24% 2,6-dihydroxybenzaldehyde a la Reimer-Tiemann.
(JACS 105, 7, 1983, 2018-2021)
Naturf.Med.Dtschld.1939-1946,Bd.37 Angew.Chem.; 53; 1940; 241,243
J.Chem.Soc.Perkin Trans.1 1988; 839-862;
JACS 103, 23, 1981, 6885-6888;
Synth.Commun. 18, 2, 1988, 191-196; J.Chem.Soc.Perkin Trans.1 19, 1997, 2925-2930;
Tetrahedron: Asymmetry 8, 20, 1997, 3415-3420)
drone 342
Member posted 11-24-98 08:30 PM
----------------------------------------
Of course, formylation could done equally successfully using DMF rather than formylalanine. Sort of a variation on the Vilsmeyer, it looks to me.
Shamelessly showing off,
Rhodium
Administrator posted 11-24-98 10:19 PM
----------------------------------------
Yup, if you tell me why the NBS would brominate in the para position rather than in one of the vacant meta, as I am led to believe.
Rhenium
Member posted 11-25-98 01:52 AM
----------------------------------------
Rhodium,
A possible alternative (which I admit is based on a lot of speculation on my part) is to go via 3,4,5-Trimethoxybenzaldehyde.
Our esteemed collegue Labrat suggested this here to get the 2,4,6-substituted materials.
(I hope that link works...)
Now, the speculative part is how to substitute the new methyl group for the bromine atom. I'll try and find a method, but as yet I don't really know. (I'll try March first).
Whilst I realise this isn't exactly OTC chemistry, not every street punk would want to make this compound. 3,4,5-Trimethoxy benzaldehyde is easily and legitimately available from the right sources. (I've currently got about 1 kg sitting under my bed).
Sorry I couldn't be more helpful, but options are options I guess and the more the better.
Rhenium
Member posted 11-25-98 03:08 AM
----------------------------------------
This is unrelated to the topic, sorry.
Drone, can you please email me, I'm thinking about dreaming of the enolate method and would appreciate your input. Send your PGP key and I'll get back to you ASAP.
Rhodium
Administrator posted 11-25-98 03:48 PM
----------------------------------------
Rhenium: The Labrat method won't work at all. First, there is no way of converting a methyl to a bromine, and using 3,4,5-trimethoxybromobenzene as starting material will only give polymerization when adding the Na. Perhaps if one would start with 3,4,5-trimethoxynitrobenzene (NO2 => NH2 => N2+ => Br) but then we are using a lot of synthetic steps again, and we still have the problem that his method is only good for making 2,4,6-substituted amphetamines, not phenylethylamines.
drone 342
Member posted 11-25-98 04:07 PM
----------------------------------------
Rh,
Hm, well, you got me there. I know it works for situations like 2,6-dimethoxyphenol, but phenols are a different animal, I guess. This is the most electron-deificient spot on the ring, and that's going to make it a pain in the ass for electrophicic additions.
Agric.Biol.Chem. 55, 5, 1991, 1333-1341. In it, they react a 2,6-dihydroxyphenylalkane with clhorotriisopropyl silane in a multistep reaction, along with an iodine source (NaI?). I haven't read it yet, but it looks like our best bet. True, halosilanes are a little exotic, but I don't make the rules now, do I? Assumedly, you could substitute NaBr for KI and get the bromo-.
Rhodium
Administrator posted 11-25-98 06:08 PM
----------------------------------------
Oh no, with (i-Pr)3SiCl, the nitrogen probably must be protected first. Sigh. Then we have a, let's see, 5-step reaction, counting the bromination as one. The best thing this far.
Osmium
Member posted 11-27-98 02:29 AM
----------------------------------------
I was thinking really hard about that yesterday in my bathtub, and I had the following ideas. More than 5 steps, but maybe my ideas will help somebody to come up with a better idea.
A) Phenolic hydroxies can be exchanged with Br by using PhPBr2 (which is not so bad as it looks; Fluka has it). Somebody has an idea how to use this here?
JACS 86, 964 (1964)
Tet Lett 1964, 2509
JOC 32, 1607 (1967)
4-NO2-toluene ---> 2,6-di-Br-4-NO2-toluene (I)
(I) ---> 2,6-di-MeO-4-NO2-toluene (II)
(II) ---> 2,6-di-MeO-4-NH2-toluene (III)
(III) ---> 2,6-di-MeO-4-Br-toluene (IV)
(IV) ---> 2,6-di-MeO-4-Br-benzaldehyde (V)
(VI) ---> 2,6-di-Br-4-NHCHO-toluene (VII)
(VII) ---> 2,6-di-MeO-4-NHCHO-toluene (IIX)
(IIX) ---> 2,6-di-MeO-4-NH2-toluene (III)
(I) ---> 3-Br-5-NO2-phenol (II)
(II) ---> 3-NO2-5-MeO-phenol (III)
(III) ---> 1,3-di-MeO-5-NO2-benzene (IV)
(IV) --lithilate, DMF-> (V)
(V) --reduce NO2, Sandmeyer--> 2,6-di-MeO-4-Br-benzaldehyde
Rhodium
Administrator posted 11-27-98 02:05 PM
----------------------------------------
Okay, thanks. My original thinking shrunk down to this approach:
(a) Nitrobenzene (I) ==Brominate==>
(b) 3,5-Dibromo-nitrobenzene (II) ==NaOMe=>
(c) 3,5-Dimetoxy-nitrobenzene (III) ==Lithiate/DMF==>
(e) 2,6-Dimetoxy-4-nitro-benzaldehyde (IV) ==Reduce/Sandmeyer==>
(f) 2,6-Dimethoxy-4-bromo-benzaldehyde (V) ==MeNO2/NH4OAc==>
(g) 2,6-Dimethoxy-4-bromo-nitrostyrene (VI) ==LAH==> pseudo 2C-B (VII)
drone 342
Member posted 11-28-98 11:30 AM
----------------------------------------
It will never be as cheap and easy as 2C-B; the chemistry and geometry of the whole 2,4,5 configuration is far simpler than the 2,4,6's. Shulgin mused about this on a couple occasions in his book.
Still, protecting the amine is as simple as acetylation, and deprotecting is nothing fancier than hydrolysis.
drone 342
Member posted 11-28-98 02:13 PM
----------------------------------------
I did a little check-up on the nitro-directed aromatic addition reactions, and a few things popped up.
Here's a whole new approach, complete with gleanings from Beilstein:
RJ.Chem.Soc.; 1927; 252;
J.Chem.Soc.; 1927; 251, 253;
J.Amer.Chem.Soc.; EN; 105; 2; 1983; 265-279;
Recl.Trav.Chim.Pays-Bas; EN; 111; 1; 1992; 22-28;
3)methoxylation, using CuBr as a catalyst, DMF as the solvent, and MeOH as the reagent. 110 deg C, 6 h, 95% yields
Tetrahedron; EN; 45; 17; 1989; 5565-5578;
Tetrahedron Lett.; EN; 34; 6; 1993; 1007-1010;
drone 342
Member posted 11-28-98 03:06 PM
----------------------------------------
Sorry about that; of course, nitro's need to be reduced before they can do the Sandmeyer cha-cha. This means there's still 5 distinct steps, but at least they're all easy.
-drone #342
drone 342
Member posted 11-29-98 05:48 PM
----------------------------------------
Does anybody have any bright ideas on how to go from the nitro- to the bromo- in the 4-position in any slick manner? If *that* could be done, this would be one kick-ass method, and would rival 2C-B for simplicity.
-drone #342
Osmium
Member posted 11-30-98 03:27 AM
----------------------------------------
" It is possible to replace a halogen on a ring by another halogen [1] if the ring is activated. There is an equilibrium, but it is usualy possible to shift this in the desired directon by the use of an excess of added halide ion [2].
Another common leaving group is nitro, which can be replaced with chloro by use of NH4Cl, PCl5, SOCl2, HCl, Cl2 or CCl4. Some of these reagents operate only at high temperatures and the mechanism is not always nucleophilic substitution. Activate aromatic nitro compounds can be converted to fluorides with F(-) [3]...
Halide exchange is particularly useful for putting fluorine into a ring, since there are fewer ways of doing this than for the other halogens. Activated aryl chlorides give fluorides when treated with KF in DMF, Me2SO, or dimethyl sulfone [4]. Halide exchange can also be accomplished with copper halides. The leaving-group order in this case is I > Br > Cl >> F. However, Ar-I have been prepared from bromides, by the use of Cu supported on charcoal or Al2O3 [5], and by treatment with excess KI and a nickel catalyst.[6]"
Jerry March, Advanced Organic Chemistry, chapter about aromatic nucleophilic substitution.
Tet. Lett. 1985, 26, 2233
Bull. Chem. Soc. Jpn. 1990, 63, 2010
Chem. Ber. 1991, 124, 157
Chem. Ind. (London) 1962, 1328
J. Fluorine Chem. 1972, 2, 19
Tet. Lett. 1989, 30, 1271
Chem. Lett. 1988, 1355 (uses PTC)
Chem. Ind. (London) 1986, 518-523
Lilienthal
Member posted 11-30-98 02:59 PM
----------------------------------------
What do you think about 4-Acetoxy-2,6-dimethoxy-phenylaceton as an intermediate? A phenolic OH can be converted to Br with PBr5.
(Indian J. Chem. 2, 374 1964 G.Singh et al.)
Beagle
Member posted 11-30-98 03:35 PM
----------------------------------------
The replacement of phenolic -OH w/ Br either by PBr5 or PhPBr2 is news to me. These methods are not generally applicable are they? I would imagine that they are useful only for very activated rings.
drone 342
Member posted 11-30-98 03:59 PM
----------------------------------------
Os,
Thanks ever-so-much for finding that J. Chem. Soc. Chem. Commun. 1983, 108 article on the substitution-elimination reaction. The question on my mind is: could bromination be accomplished in a similar way, or would one still have to go through the second step?
drone 342
Member posted 11-30-98 04:00 PM
----------------------------------------
Os,
Thanks ever-so-much for finding that J. Chem. Soc. Chem. Commun. 1983, 108 article on the substitution-elimination reaction. The question on my mind is: could bromination be accomplished in a similar way, or would one still have to go through the second step?
Lilienthal
Member posted 12-01-98 06:17 AM
----------------------------------------
Sorry, yes - for the nucleophilic aromatic substitution (OH -> Br) you need strong -M groups like NO2 in the ortho or para position (I only had some references on phenol to bromobenzene with PBr5). Instead, we may use the 4-Acetoxy-2,6-dimethoxy-phenylaceton as an intermediate for 4-ethers... I found this substance during a Beilstein search, but had no time to look into the article yet.
drone 342
Member posted 12-01-98 03:26 PM
----------------------------------------
Making 4-acetoxyPEA is harder to do than simply making 4-nitroPEA. I think it'd be harder to convert to a bromo as well.
-drone #342
drone 342
Member posted 12-02-98 04:40 PM
----------------------------------------
Hm, in PiHKAL, Shulgin says that the 2,6's, or as he calls them, the pseudo 2C's, should yield just as many fascinating compounds as the original 2C's. He went through the time and effort to do the herculean task of synthesizing and investigating the 2,5-dimethoxy-4something-or-other-PEA's,
So let's see what we have so far. Dr. Shulgin (I feel so wierd anonymously calling him "Sasha"; we've hardly even met in real life, anyway), already did Psi-2C-T-4, as well as Psi-2C-D, and Psi-2C-P. We can assume, using the same techniques for the Psi-2C-T-4 and Psi-2C-P, you could make the other 4-alkoxy- and 4-alkyl-substituted products, respectively using a similar synthetic route. By nitrating PEA in the 4-position, then brominating it in the 2 and 6 positions, them methoxylating, we have Psi-2C-N. Reducing the nitro to a chloro will yield Psi-2C-C, and substituting the chloro with other halides yields the Psi-2C-B we were orignially intersted in, as well as Psi-2C-I, if we so wish.
drone 342
Member posted 12-02-98 06:10 PM
----------------------------------------
Lilienthal,
Something's been bugging me since yesterday, but I just remembered now to say something. Acetoxy groups aren't very good for meta-directing. They aren't that electron-withdrawing. Now if the carbonyl were directly attached, yes, but then it would be a phenyl ketone, and we have a this is a phenyl ester, and the electronegativity of the carbonyl is not going to play a big enough role for what we're doing. While using this as the starting material was hypothetical at best, I just had to get that off my chest.
drone 342
Member posted 12-10-98 08:15 PM
----------------------------------------
Osmium,
Seeing that I don't have a copy of Jerry March's book handy, could you tell me specifically which references were associated with the substitution of a chlorine for a nitro group on an aromatic species. For the life of me, I can't quite understand how it was written, and I can only find one other ref for this procedure:
drone 342
Member posted 12-13-98 01:38 PM
----------------------------------------
Rhodium,
You've definately got my imgaination captured with this thread! I finally remembered this morning to check out Larock's Comprehensive Organic Transformations regarding the ceonversion of the nitro into a bromo. With this tidbit in hand, the synthesis of psuedo-2C-B becomes nitration of PEA, bromination of nitro PEA, methoxylation to make pseudo-2C-N, then this final substitution reaction: 4 steps!!! That's as simple, or simpler than 2C-B itself! Here's a list of essentially 1-step procedures for the final substitution reaction, and their correspoinding reagents. Many of these look quite exciting, since the reagents are all so inexpesive and common.
HBr, NaNO2/CuBr Org. Syn. Coll. Vol. 3, 185 (1955)
JACS 109, 3378 (1987)
H2SO4, NaNO2/CuBr JOC 51, 1339 (1987)
AmONO, CHBr3 JCS C 1249 (1966)
t-BuONO, CuBr2 JOC 42 (1977)
t-BuSNO2, CuBr2 BCJS 53 2023 (1980)
Hg2Br, heat Ber. 65 1605 (1932)
KBr, H2SO4/NaNO2/Cu Ber 1220 (1890)
HNO2/Et2NH/TMSCl, LiBr JOC 46 5239 (1981)
drone 342
Member posted 12-13-98 01:41 PM
----------------------------------------
damn! What a mistake! We're still using five steps: the nitro has to be reduced to an amine before any of those ref's I gave will do anything useful. Still, nitro's are readily reduced by just about anything, so a little iron powder or alumina ought to do the trick.
Rhodium
Administrator posted 12-13-98 10:10 PM
----------------------------------------
But the nitration of PEA aren't going to be selective at the 4-position, or? And don't you think the aliphatic amine needs to be protected before going through all those steps?
drone 342
Member posted 12-15-98 02:49 PM
----------------------------------------
Nitration *can* be selective, and in fact, it is fairly so using the techniques described in the methods I listed -- provided a person is careful in their nitration, the para position is much more favored than ortho. The amine would not have to be protected at all, as far as I can see; nitration doesn hurt it, bromination doesn hurt it, the aromatic substitution-elimination won't hurt it, reduction is obviously safe, and even the last step is one pertaining to aryl amines. So, it should be just fine hanging out there.
-drone #342
Lilienthal
Member posted 12-15-98 04:05 PM
----------------------------------------
Short idea, no refs: don't put DMF on your lithiated 3,5-dimetoxy-1-XXX-benzene, try 1-Br-2-dimethoxy propane (or another acetale of 1-halogen acetone). After deprotecten you should have the phenylacetone...
Rhodium
Administrator posted 12-16-98 01:44 AM
----------------------------------------
Other alternatives for producing amphetamine precursors would be to use 1,2-dibromopropane (product: the phenyl-2-bromopropane) or epichlorohydrin (product: the P2Pol), but the original question was how to produce the phenethylamine, not the amphetamine.
