Well, got a lot of junk for y'all, but been having trouble uploading. Some good refs and info, dealing with the matter at hand. 4 pages of it, in fact, so stay tuned. But for now, satisfy your hunger with this illustration.
The route, illustrated for your viewing pleasure.
aspartame hydrolyzes to phenylalanine
Molecule: (https://www.the-hive.ws/forum/faq.pl?Cat=#applet)
aspartame ("OC(=O)CC(N)C(=O)NC(C(=O)OC)Cc1ccccc1>>NC(C(=O)O)Cc1ccccc1")
phenylalanine decarboxylates to phenethylamine
Molecule: (https://www.the-hive.ws/forum/faq.pl?Cat=#applet)
phenylalanine ("NC(C(=O)O)Cc1ccccc1>>NCCc3ccccc3")
phenethylamine cyclizes with acetone and formaldehyde to phenethylpiperidone, via Mannich reaction
Molecule: (https://www.the-hive.ws/forum/faq.pl?Cat=#applet)
phenethylamine,acetone,formaldehyde ("N(CCc3ccccc3).CC(=O)C.C=O.C=O>>c2(CCN(CCc3ccccc3)CC2)=O")
phenethylpiperidone is condensed with nitromethane to give a nitrostyrene
Molecule: (https://www.the-hive.ws/forum/faq.pl?Cat=#applet)
to nitrostyrene ("c2(CCN(CCc3ccccc3)CC2)=O.CN(=O)=O>>c2(CCN(CCc3ccccc3)CC2)=CN(=o)=o")
which is then attached to aniline via Michael addition
Molecule: (https://www.the-hive.ws/forum/faq.pl?Cat=#applet)
conjugate addition ("C2(CCN(CCc3ccccc3)CC2)=CN(=o)=o.Nc4ccccc4>>c1ccccc1NC2(CCN(CCc3ccccc3)CC2)CN(=o)=o")
The nitro group is then either oxidized or hydrolyzed to give a carboxylic acid
Molecule: (https://www.the-hive.ws/forum/faq.pl?Cat=#applet)
almost there ("c1ccccc1NC2(CCN(CCc3ccccc3)CC2)CN(=o)=o>>N(c1ccccc1)c2(CCN(CCc3ccccc3)CC2)C(=O)O")
Which is then esterified with methanol
Molecule: (https://www.the-hive.ws/forum/faq.pl?Cat=#applet)
closer... ("N(c1ccccc1)c2(CCN(CCc3ccccc3)CC2)C(=O)O>>N(c1ccccc1)c2(CCN(CCc3ccccc3)CC2)C(=O)OC")
And finally, propionic anhydride is added
Molecule: (https://www.the-hive.ws/forum/faq.pl?Cat=#applet)
carfentanyl ("N(c1ccccc1)c2(CCN(CCc3ccccc3)CC2)C(=O)OC>>CCC(=O)N(c1ccccc1)c2(CCN(CCc3ccccc3)CC2)C(=O)OC")
And there it is.
By the way, Rhodium: I have a really cool thesis that might answer some of your questions. Shortly the relevant parts will bee posted here. :)
Here is the info, as promised:
First, a snippet from my ever-so-useful Chemistry of Organic Compounds, 1951, regarding the formation of the piperidone ring via Mannich reaction(Step 2a):
Pg. 705
"
The beta-amino ketones are sufficiently stable to be isolated in the free state. They may be prepared by the addition of ammonia or primary or secondary amines to alpha,beta-unsaturated ketones (pg. 703).
Substituted beta-amino ketones can be prepared by the Mannich reaction (p. 494). Thus dialkyl- and alkylarylamino ketones result from the condensation of secondary amines with formaldehyde and ketones.
R.CO.CH2.R' + H2C=O + HN.R2 --> R.CO.CH(R').CH2.N.R2
The amine usually is used in the form of the hydrochloride or the reaction may be carried out in glacial acetic acid. Aromatic aldehydes may be used instead of formaldehyde. to give aryl substituted products. If a primary amine is used instead of a secondary amine and the ketone contains a hydrogen on both alpha-carbon atoms, a cyclic compound results.
Molecule: (https://www.the-hive.ws/forum/faq.pl?Cat=#applet)
piperidone! ("CN.C=O.C=O.CC(=O)C>>CN1CCC(=O)CC1")
"
Yes! Exactly what I meant to say! And believe it or not, that is the exact graphic in the book! Any doubters? Find a copy for yourself, it's a really useful book.
Now for the condensation of cyclic ketones with nitromethane (Step 3a):
If we condense the nitromethane and piperidone first to a nitrostyrene, then perhaps we can perform a Michael addition to the conjugated double bond.
Synthetic Communications 2000, 2071 : Gel entrapped base catalyzed henry reaction : synthesis of conjugated nitroalkenes
Molecule: (https://www.the-hive.ws/forum/faq.pl?Cat=#applet)
cyclohexanone to nitrostyrene ("O=C1CCCCC1.CN(=O)=O>>C1CCCCC1=CN(=O)=O")
Yield was 56%, not so good, reaction time was 15 minutes, and base catalyst was NaOH gelled with agar. Other papers do better, like the tetrahedron paper mentioned earlier. Conjugated position is preferred for the double bond, because it is the lowest energy state. With molecular sieves or dean-stark trap to take up the water released, yields will surely be better. As the making of nitrostyrenes is a common operation for bees, there should be lots of expertise around here about how to get high yields, etc.
Then we have the second part, the Michael addition of the aryl amine to the conjugated double bond:
Molecule: (https://www.the-hive.ws/forum/faq.pl?Cat=#applet)
Michael addition to PhN (" C1CC(CCN1C)=CN(=O)=O.Nc1ccccc1>>C1CC(CCN1C)(CN(=O)=O)Nc1ccccc1")
With addition of heat, and maybe a little basic catalyst, the amine adds to the nitrostyrene at the beta-position. In the old Chemistry of Organic Compounds book, it says on p. 703, referring to alpha-beta unsaturated carbonyl compounds:
"Ammonia, which does not form stable addition products with the carbonyl group, gives beta-amino ketones. The addition product of ammonia and mesityl oxide is called diacetonamine.
Me2.C=CH.CO.CH3 + NH3 --> Me2.C(NH2).CH.CO.CH3
Phorone (p. 205) adds two moles of ammonia to give triacetonediamine, which on heating cyclizes to triacetonamine.
Molecule: (https://www.the-hive.ws/forum/faq.pl?Cat=#applet)
Michael addition I ("CC(C)=CC(=O)C=C(C)C>>CC(C)(N)CC(=O)CC(C)(N)C")
Molecule: (https://www.the-hive.ws/forum/faq.pl?Cat=#applet)
Cylclization II ("CC(C)(N)CC(=O)CC(C)(N)C>>N1C(C)(C)CC(=O)CC1(C)C")
hey, isn't that TEMPO?
Anyway, this is very suggestive, and the addition issue is no problem for us; since we are not using a carbonyl compound, there's no way the aniline will attach onto the nitro group.
JOC 1958, 729 says "ammonia added readily to I to form tris(2-sulfamylethyl)amine"
Molecule: (https://www.the-hive.ws/forum/faq.pl?Cat=#applet)
conj. alkene adding to ammonia (" C=C-S(=O)(=O)-N.C=C-S(=O)(=O)-N.C=C-S(=O)(=O)-N.N>>N(CC-S(=O)(=O)-N)(CC-S(=O)(=O)-N)CC-S(=O)(=O)-N")
Basically, they just let it sit with ammonia overnight. No yield given, but you get the idea it was quantitative.
JACS 1950, 3298 says "The substances included were all synthesized by reaction of the appropriate amine with methyl acrylate giving excellent yields in most cases"
Molecule: (https://www.the-hive.ws/forum/faq.pl?Cat=#applet)
methyl acrylate adds to primary and secondary amines (" c1ccccc1CNCCC(=O)OC.C=CC(=O)OC>>c1ccccc1CN(CCC(=O)OC)CCC(=O)OC")
this one got 80% yield, but the yields are sort of funny. When the amine was in a saturated heterocyle, yields were from 90 to 100% (!). When the amine was primary, or secondary with a really short second group, the yields sucked (37%, 44%). One factor is that these two compounds were stated to have "intractable hydrochloride salts", indicating that they may have gotten those low yields due to trouble with crystallization.
In McMurry 4th, on page 915 (The Michael Reaction), we can see a table listing Michael acceptors and donors. One of them is nitroethylene. (C=CHNO2) Apparently, nitrostyrene is an even better Michael acceptor than an acrylate, because the nitro group spreads charge better than a carbonyl, giving a stronger acidity to its alpha carbons. The nitro form of a nitroalkane has a pKa around 9, while its aci form has a pKa from 2 to 6. (wow!) This makes it very easy to attack.
Furthermore, since the Michael addition is just a special class of nucleophilic addition to a conjugated bond, let's turn to page 750, where we will see, in the chapter on Conjugate Nucleophilic Addition to a,b-Unsaturated Carbonyl Groups, this:
"Conjugate Addition of Amines
Primary and secondary amines add to a,b-unsaturated carbonyl compounds to yield beta-amino ketones and aldehydes. Reaction occurs rapidly under mild conditions, and yields are good. Note that, if only one equivalent of amine is used, the conjugate addition product is obtained to the complete exclusion of the direct addition product."
Molecule: (https://www.the-hive.ws/forum/faq.pl?Cat=#applet)
Conjugate addn. I ("CC(=O)C=C.CCNCC>>CC(=O)CCN(CC)CC")
3-Buten-2-one + Diethylamine --EtOH--> 4-N,N-Diethylamino-2-butanone (92%)
Molecule: (https://www.the-hive.ws/forum/faq.pl?Cat=#applet)
Conjugate addn. II ("O=C1C=CCCC1.CN>>O=C1CC(CCC1)NC")
2-Cyclohexanone + Methylamine --EtOH--> 3-(N-methylamino)cyclohexanone
Note that the second one is cyclic, like our carfentanyl nitrostyrene.
Also, while browsing the net, I found this in a thesis by James K Murray Jr, for Drexel University.
It is here (http://dspace.library.drexel.edu/retrieve/1448/)
(http://dspace.library.drexel.edu/retrieve/1448/). I quote, from page 135:
"A one-pot, three step sequence of nitroaldol formation, dehydration, and Michael addition is often used to avoid potential problems with the nitroalkenes, which are often prone to polymerization or decomposition. As with the nitroaldol reaction, Michael additions of nitroalkenes and nitroalkane anions find their major synthetic utility in the numerous transformations that the Michael adducts can undergo, primarily involving the nitro group. Various oxygen, sulfur, nitrogen, and phosphorus nucleophiles can be employed in conjugate additions to nitroalkenes (eqn. 2.31).
Molecule: (https://www.the-hive.ws/forum/faq.pl?Cat=#applet)
eqn.2.31 ("CC(C)=C(C)N(=O)=O.N(C)C>>CC(C)(C(C)N(=O)=O)N(C)C")
These reactions are operationally simple: the nitroalkene and nucleophile are mixed in the presence of base and the conjugate addition products are formed. (...) The same bases that are typically employed in the nitroaldol reaction, alkali metal hydroxides or alkoxides and tertiary amines, are also suitable for Michael additions to nitroalkenes."
However, (pg. 140)
"The direct addition of nitrogen nucleophiles to nitroalkenes is not often a synthetically useful reaction, since the reaction tends to be reversible favoring the nitroalkene. To incorporate nitrogen nucleophiles, an addition/elimination sequence is generally used, as shown in Equation 2.41 for the preparation of 361.
Molecule: (https://www.the-hive.ws/forum/faq.pl?Cat=#applet)
eqn 2.41 ("c1ccccc1SC=CN(=O)=O.N2CCCC2>>C2CCCN2C=CN(=O)=O")
THF, RT 2hr"
I don't know what he is talking about, since in his figure, a conjugate addition is clearly not being performed. At the very least, this is very confusing language, especially in light of the VERY NEXT FIGURE:
"Chiral nitrogen nucleophiles, common sources of asymmetric induction, can be added to nitroalkenes, followed by rapid reduction of the nitro group with samarium(II) iodide, as a simple method for the synthesis of non-racemic 1,2-diamines such as 364 (Equation 2.42)
Molecule: (https://www.the-hive.ws/forum/faq.pl?Cat=#applet)
eqn 2.42 (" O=N(=O)C1=CCCCC1.OCC2CCCN2>>OCC3CCCN3C4CCCCC4N(=O)=O")
CH2Cl2, RT 30 min, 95%
"
And the reduction is in a different step. Now it seems very unlikely that that little OH makes all the difference between the reaction not working at all, and giving almost quantitative yield in 30 minutes at room temperature, so I'm going to assume that, for some reason, in the first case he was trying to add without disturbing the double bond, and in the second case he was doing a direct addition.
So that's what I have on the condensation and conjugate addition steps, and though not overwhelmingly convincing, it's very encouraging.
Finally, here's another snip from my venerable Chem. of Org. Cmpds. book on obviating the permanganate oxidation of nitro-ANPP to carfentanyl-minus-methyl-ester. I think it's called the nef reaction:
Pg. 256
"
5. Acid Hydrolysis.
(a) Hydrolysis of the nitro form of a primary nitro compound.
When primary nitro compounds are boiled with concentrated aqueous hydrochloric acid, carboxylic acids and hydroxylamine hydrochloride are formed.
R.CH2.NO2 + HCl + H2O --> R.COOH + HONH3.Cl
By this reaction, which involves an oxidation of the methylene group and reduction of the nitro group, carboxylic acids may be prepared from hydrocarbons. The price of hydroxylamine, which was produced by the reduction of nitrous acid and isolated by way of acetoxime (p.207), has been reduced greatly because of the above process.
(b) Hydrolysis of the aci form of a primary or secondary nitro compound.
If a primary or secondary nitro compound first is converted to the salt of the aci form by alkali and then hydrolyzed by 25% sulfuric acid, aldehydes and ketones are produced with the evolution of nitrous oxide (Nef reaction, p. 354).
2 R2.C=NOONa + 2 H2SO4 --> 2 R2.C=O + N2O +2 NaHSO4 + H2O
"
Well, that's how it stands right now. After all this searching and reading and printing, I am further convinced that the proposed reaction is both reasonable and will work well in practice. Hope this long, boring drone will be of some use to inquiring minds. :) Wherever did our dear Drone go off to? :(
This one goes out to the silent masses out there. Yes, you know who you are. Ning, having been faced with some harsh, but true, criticism of his eeevil opioid synth, is back with revisions to make the impossible...practical. We hope.
First the route:
Reflux the nitrostyrene obtained by knoevenagel condensation of nitromethane and piperidone in concentrated aqueous HBr, to give a bromo-carboxylic acid. It would be a lachrymator, but it surely is too heavy to evaporate well.
Molecule: (https://www.the-hive.ws/forum/faq.pl?Cat=#applet)
The first magic... ("c1ccccc1CC-N1CCC(CC1)=CN(=O)=O>>c1ccccc1CC-N1CCC(CC1)(Br)-C(=O)O")
JCS Perkin I 1981, 2520
JCS 1911, 1514
JCS 1931, 952
And best of all, (if I could get it!!!)
Collect. Czech. Chem. Commun. 1983, 2952
Then a small esterification step, MeOH/H2SO4:
Molecule: (https://www.the-hive.ws/forum/faq.pl?Cat=#applet)
Methylation ("c1ccccc1CC-N1CCC(CC1)(Br)-C(=O)O.OC>>c1ccccc1CC-N1CCC(CC1)(Br)-C(=O)OC")
Now, you can attach the ANILIDE you made previously, without fear of hydrolysis! Concentrated methanolic NaOH comes to mind, perhaps with a bit of PTC thrown in for good measure.
Molecule: (https://www.the-hive.ws/forum/faq.pl?Cat=#applet)
The second magic... ("c1ccccc1CC-N1CCC(CC1)(Br)-C(=O)OC.c1ccccc1NC(=O)CC>>c1ccccc1CC-N1CCC(CC1)(N(c1ccccc1)C(=O)CC)-C(=O)OC")
To see this done, see JMC 1970, 559 where yield was 70-94% for an iodide attaching to a substituted acetanilide.
Also:
Justus Leibig's Annalen 1889, 321
JCS 1947, 1486
Russian Journal of Organic Chemistry 1998, 494 (528)
(actually, the refs for the previous 2 steps might bee reversed. Sorry if this causes trouble, will edit as soon as I'm sure)
So, why do we do this in such a backwards manner?
So we can dispense with the propionic anhydride:
Molecule: (https://www.the-hive.ws/forum/faq.pl?Cat=#applet)
No propionic anhydride! ("c1ccccc1N.CCC(=O)O>>c1ccccc1NC(=O)CC")
I have refs for this too, but not right now. It's relatively easy, you just reflux aniline and propionic acid. Water is evolved. If you like, you can drive it all the way to completion by using a column set to 100 C at the top.
And finally, how to get aniline, OTC.
Molecule: (https://www.the-hive.ws/forum/faq.pl?Cat=#applet)
KMnO4 oxidation of toluene ("c1ccccc1C>>c1ccccc1C(=O)O")
Molecule: (https://www.the-hive.ws/forum/faq.pl?Cat=#applet)
Ammonium Benzoate heated > 100 C ("c1ccccc1C(=O)[O-].[N+]>>c1ccccc1C(=O)N")
Molecule: (https://www.the-hive.ws/forum/faq.pl?Cat=#applet)
NaOCl hoffmann rearrangement ("c1ccccc1C(=O)N>>c1ccccc1N")
The permanganate oxidation of toluene is covered well. If refs wanted, I'll get some.
The heating dehydration of carboxylic acid ammonium salt to give amide is also well covered. In fact, this synth relies on it to give the anilide as well.
See Org. Syn CV2, pg. 44 "4-aminoveratrole", where they do exactly that hoffmann rearrangement of amide to an aniline, with NaOH/NaOCl. Yield 80%
What this means is that from toluene, or from benzoic acid/sodium benzoate (common food preservatives) and household ammonia, you can make aniline.
From methyl ethyl ketone and bleach, you can make propionic acid.
From aniline and propionic acid, you can have propionanilide. And with the piperidone thoroughly beaten on in previous posts, from fake sugar, formaldehyde and acetone, plus a little methanol, racing fuel and NaBr from the pool supply, you're set with carfentanil. By performing the addition/hydrolysis simultaneously and before the addition, we should be able to dodge the "delicate amide doesn't like acid" issue.
Ning feels like the gods and demons of drug chemistry want this synth to happen--there's always another way around the obstacles nature and man throw up before us. That's part of the thrill, isn't it?
Thanks guys, for teaching ning about "hoffmann rearrangement" :)
carfentanil synth V2 refs:
<F1> : Penultimate assembly, formation of propionanilide
Molecule: (https://www.the-hive.ws/forum/faq.pl?Cat=#applet)
step F1 ("c1ccccc1N.OC(=O)CC>>c1ccccc1NC(=O)CC")
Journal of the American Chemical Society 1940, 3523. New Compounds.
N-(2,4-Xylyl)-propionamide
N-(2,5-Xylyl)-propionamide
N-(2,6-Xylyl)-propionamide
The propionamides were obtained by refluxing the amine and propionic acid for several hours.
Journal of the Chemical Society 1898, 33. Decomposition of Camphoric Acid by Fusion with Potash or Soda.
The fraction 135-150 C contains propionic acid, CH3.CH2.COOH.--
After repeated very careful fractionation with a column, an acid was isolated which distilled constantly at 140 C, and was evidently propionic acid. The anilide of this acid was prepared by heating it with aniline and recrystallizing the product from light petroleum (bp 100-120); the white plates thus obtained were almost insoluble in water, more soluble in light petroleum, and very soluble in alcohol and ether. The substance melted at 103-104 C. The melting point of propionanilide as given by Sestini (Zeitschrift fur Chemie, 1871, 35) is 92 C, and by Kelbe (Ber., 1883, 16, 1200) as 105 C. A specimen of the anilide which we prepared from pure propionic acid and pure aniline melted at 103-104 C, and was identical with the anilide obtained by us as described above.
Journal of the Chemical Society 1908, 1033. Melting Points of the Anilides, etc. of Fatty Acids.
Propionic acid--
Amide: melts 79
Anilide: melts 105
p-toluidide: melts 123
The anilides, p-toluidides, and a-napthalides described in the present paper were prepared by the following method. A mixture of 1 to 3 grams of the fatty acid and the equivalent amount of amine were heated in a sealed tube to 160-190 C for eight to twelve hours. In no case was any pressure observed in the tube after cooling. The product of the reaction, generally a solid or an oil which soon solidified, was purified by recrystallization from aqueous alcohol, or, in the case of the derivatives of the higher fatty acids, absolute alcohol. In certain cases, when the product tended to be oily, it was found advisable to first spread the mass on a porous tile and leave for 24 hours before recrystallization. The yields varied between 30 and 80 per cent, depending largely on the degree of purity of the fatty acid employed. The anilides and p-toluidides were pure white or faintly yellow; the a-napthalides generally had a pink color, not unlike that which a-napthylamine acquires on contact with the air. On boiling in alcoholic solution with animal charcoal, all traces of pink colour could be removed without, however, affecting the melting point. When pure, the a-napthalides were completely free from the objectionable odor of the base.
Merck Index 8th ed. 1968
Aniline melts at -6 and boils at 184.
Propionic acid melts at -21 and boils at 141.
Suggestively, aniline acetate spontaneously converts to acetanilide with age.
<F2> : Final assembly, N-alkylation of propionanilide
Molecule: (https://www.the-hive.ws/forum/faq.pl?Cat=#applet)
Step F2 ("c1ccccc1CCN(CC2)CCC2(Br)C(=O)OC.N(C(=O)CC)c3ccccc3>>c1ccccc1CCN(CC2)CCC2(N(C(=O)CC)c3ccccc3)C(=O)OC")
Journal of Medicinal Chemistry 1970, 539. Felder, Pitre, Fumagalli, Lorenzotti. Radioopaque Contrast Media. XVIII. Derivatives of 2-(3-amino-2,4,6-triiodophenyl)alkanoic Acids.
Molecule: (https://www.the-hive.ws/forum/faq.pl?Cat=#applet)
Yield 87% ("OC(=O)Cc1c(I)cc(I)c(c1I)NC(=O)CCC.ICCCC>>OC(=O)Cc1c(I)cc(I)c(c1I)N(C(=O)CCC)CCCC")
Molecule: (https://www.the-hive.ws/forum/faq.pl?Cat=#applet)
Yield 95% ("OC(=O)Cc1c(I)cc(I)c(c1I)NC(=O)CCC.ICc1ccccc1>>OC(=O)Cc1c(I)cc(I)c(c1I)N(C(=O)CCC)Cc2ccccc2")
2-(3-Alkylacylamino-2,4,6-triiodophenyl)alkanoic Acids:
A solution of 0.045 mol of alkyl iodide in 2.5 ml of acetone was added for 30 minutes to a solution of 0.03 mol of 2-(3-acylamino-2,4,6-triiodophenyl)alkanoic acid and 0.12 mol of KOH in 35 ml of H2O. The mixture was stirred for 4 hr at 35 C and then poured into 200 ml of ice water and extracted twice with ether (30 ml). The crude product, obtained by precipitation with 18% HCl, was purified further by reprecipitation, extraction with boiling ethyl acetate, or recrystallization from a suitable solvent.
Journal of Organic Chemistry 1992, 1864. Kawabata, Minami, Hiyama. Stereoselective Synthesis of b-Lactams by Oxidative Coupling of Dianions of Acyclic Tertiary Amides.
Molecule: (https://www.the-hive.ws/forum/faq.pl?Cat=#applet)
Yield 95% ("COc1ccc(cc1)NC(=O)CCC.BrCC(=O)OC(C)(C)C>>COc1ccc(cc1)N(C(=O)CCC)CC(=O)OC(C)(C)C")
The solid (~9 mmol) dissolved in dichloromethane (20 ml) was treated with tert-butyl bromoacetate (3.08 ml, 18 mmol) and then with benzyltriethylammonium bromide (0.25 g, 0.92 mmol). To the resulting mixture was added 50% aq NaOH (1.0 ml) at 0 C. After being stirred at room temperature for 17 h, the mixture was poured into saturated NH4Cl solution and extracted with ethyl acetate. The organic phase was washed with water, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography.
<B3> : Hydrolysis and bromination, Nitromethylenepiperidine to 4-halo-piperidylacetic acid
Molecule: (https://www.the-hive.ws/forum/faq.pl?Cat=#applet)
Step B3 ("c1ccccc1CCN(CC2)CCC2=CN(=O)=O>>c1ccccc1CCN(CC2)CCC2(Br)C(=O)O")
Journal of the Chemical Society 1911, 1513. Optically Active Derivatives of 1-methylcyclohexylidene4-acetic acid.
Molecule: (https://www.the-hive.ws/forum/faq.pl?Cat=#applet)
Yield unknown ("CC1CCC(CC1)=CC(=O)O>>CC1CCC(CC1)(Br)CC(=O)O")
4-Bromo-1-methylcyclohexyl acetic acid:
A reaction which resembles the above reduction in that it should convert the centroasymmetric optically active acid into a saturated substance which is potentially optically inactive, is involved in the addition of hydrogen bromide to the 1-methylcylohexylidene-4-acetic acids. When the unsaturated dl-acid is mixed with fuming hydrobromic acid (saturated at 0 C) it dissolves, but in a short time an oil, which rapidly crystallizes, separates on the surface. The crystalline mass is washed with water, left in contact with porous earthenware until quite dry, and then recrystallized from a little formic acid, in which it is very soluble, and from which it separates, usually in plates, but sometimes in hard, brilliant prisms.
Similar experiments were made on the action of hydrobromic acid on d- and l-1-methylcyclohexylidene-4-acetic acids, and resulted in both cases in the production of an optically inactive bromo-acid identical in all respects with that obtained from the externally compensated unsaturated acid.
We have previously prepared this substance by the action of fuming hydrobromic acid on 4-hydroxymethylcyclohexyl-4-acetic acid (Trans., 1908, 93, 1082); Wallach (Annalen, 1907, 353, 312) made the same substance by treating the 1-methylcyclohexylidene-D3-acetic acid of Markwald and Meth with hydrobromic acid.
4-Methylene-1-methylcyclohexane:
Finely divided 4-bromo 1-methyl cylohexyl 4-acetic acid dissolves readily in sodium carbonate solution, but the liquid gradually clouds and an oil separates; the change occurs rapidly when the solution is warmed at 40 C. The oil is extracted with ether, the ethereal extract carefully dried and evaporated, and the residue distilled; the whole quantity passes over at 122 C. [...] There can be no doubt that this hydrocarbon is 4-methylene 1-methyl cyclohexane, and identified with the compound which Wallach obtained (Annalen, 1906, 347, 345; 1909, 365, 267) by the slow distillation both of 1-methyl cyclohexylidene 1-acetic acid, and of 1-methyl D3-cyclohexene 1-acetic acid, intramolecular change taking place in the latter case.