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:
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:
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:
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:
Michael addition I ("CC(C)=CC(=O)C=C(C)C>>CC(C)(N)CC(=O)CC(C)(N)C")
Molecule:
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:
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:
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:
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:
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/). 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:
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:
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:
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?