This'll bee another megapost, I'm afraid.
Org syn CV 7, 108http://www.orgsyn.org/orgsyn/prep.asp?prep=cv7p0108
Tetrahedron 1997, 17307 3,4,5-trimethoxyphenylacrylonitrile
In a 500 ml three-necked RBF equipped with a condenser and charging funnel were dissolved 3.3 g KOH in 200 ml acetonitrile. The funnel was charged with 9.8 g 3,4,5 trimethoxybenzaldehyde in 50 ml of acetonitrile, and the system was brought under reflux with a stream of nitrogen. The aldehyde was added in 1-2 min and after 15 min the mixture was poured into a 1 L flask with cracked ice. Extraction with ether yielded 3.2 g of crude product which was purified on silica gel to provide 2.4 g trimethoxyphenylacrylonitrile.
(ugh. Yield sucks.)
JOC 1991, 18823,4-dimethoxy 6-oxo phenyl acrylonitrile
A mixture of powdered 80% KOH (700 mg, 12.5 mmol) and dry acetonitrile (20 ml, freshly distilled from CaH2) was heated to reflux under N2, and a solution of 3,4-dimethoxy 6-dimethoxymethyl benzaldehyde (3 g, 12.5 mmol) in acetonitrile (5 ml) was added. The reaction mixture was stirred for 10 min, and the hot solution was poured onto crushed ice and extracted with DCM. The extracts were dried over Na2SO4 and concentrated, keeping the bath temperature at 30 C. The resulting yellow viscous oil was then dissolved in THF (20 ml) and stirred with 2 N HCl (10 ml) for 1 h.
<<note: to hydrolyze the acetal, not necessary for our purposes>> The usual workup followed by flash chromatography and two successive crystallizations (Chloroform and ether) afforded the title compound in 73% yield.
(in this paper, they also condense aldehydes with methyl acetate, obtaining yields ~65 %)
Eur. J. Org. Chem. 2000, 1527
Molecule:
one ("c1cc(OC)c(OC)c(OC)c1c2c(OC)ccc(c2)C=O>>c1cc(OC)c(OC)c(OC)c1c2c(OC)ccc(c2)C=CC#N")
In a 250 ml three-necked RBF, equipped with a tap funnel, a reflux condenser, nitrogen inlet, and mag stirrer, was added 85% powdered KOH (109 mg, 1.65 mmol) and dry acetonitrile (1.4 ml). The mixture was heated to reflux and a solution of aldehyde (500 mg, 1.65 mmol) in a 50:50 mixture of acetonitrile and dioxane (5.5 ml) was added in one stream. After the addition was complete, stirring was continued for 8 min and the hot solution was poured onto cracked ice (35 ml). This mixture was extracted with DCM (4 x 25 ml), dried over MgSO4 and evaporated in vacuo. Flash chromatography of the crude product gave the propenenitrile (486 mg, 91%)
Molecule:
one ("c1cc(OC)c(OC)c(OC)c1c2c(OC)ccc(c2)C=CC#N>>c1cc(OC)c(OC)c(OC)c1c2c(OC)ccc(c2)CCC#N")
To a solution of propenenitrile (440 mg, 1.35 mmol) in methanol (11 ml), magnesium turnings (658 mg, 27.66 mmol) were added cautiously in portions. An oversized flask and efficient ice/water cooling bath were required to control the foaming from the vigorous exothermic reaction. The mixture was stirred for 5 h and then acidified with 6 M HCl and extracted with DCM (4 x 25 ml). The combined organic layers were dried over MgSO4. Removal of the solvent gave the crude propanenitrile (335 mg, 80%).
JOC 1979, 4640Ok, this one is fucking awesome. I'm going to have to type it up in full, unless some bee gets the pdf or does it first. The entire article is on this kind of thing. Here's a table, to start your salivation:
Benzaldehyde Time Yield
plain 3 min 82%
2-Me 9 63%
4-Me 6 61%
4-MeO 10 81%
2,3-diMeO 3 80%
3,4--OMeO- 7 86%
There's others, of course, notably furfural (which would make a most interesting amphetamine), but to save space, I clipped them.
...blah blah blah....
Sodium hydroxide was, in general, a poorer catalyst than KOH for the condensation, but addition of either 5 mol % 18-crown-6 or 0.5 equiv water to the NaOH-containing reactions had a similar influence.
....snip snip...
Only aromatic aldehydes and ketones would react properly under these conditions (oh, such a shame)
...
General procedure for the reaction of non-enolizeable carbonyl compounds with MeCN in the presence of KOH:
A 100 ml, three-necked RBF, equipped w/ pressure-equallized addition funnel, reflux condenser, N2 purge, and mag stirrer, was charged with powdered KOH (0.01-0.05 mol) and dry MeCN (10-40 ml). The mixture was heated to reflux (~83 C), and a soln of the carbonyl compound (0.01-0.05 mol) in MeCN (10-20 ml) was added in a stream. Preparative scale reactions were normally conducted at concentrations of 0.5-1.0 M in carbonyl electrophile. After the addition was complete, stirring was continued the specified time and then the hot soln was poured onto cracked ice (100 g). This mixture was extracted with three 75-ml portions of DCM, dried over Na2SO4, and evaporated in vacuo. During evaporation, the bath temp. was maintained at ~30 C to minimize decomposition. The crude product thus obtained was purified by column chromatography (alumina, 80-325 mesh).
Prepn. of 3,4-Methylenedioxycinnamonitrile:
3,4-methylenedioxybenzaldehyde (7.5 g, 0.05 mol) was heated with MeCN (50 ml) in the presence of KOH (3.30 g,0.05 mol) for 7 min as described in the gen. procedure. After chromatography, the title compound (7.44g, 86%) was obtained as a yellow solid.
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well, that's just about it. Use the above procedures to condense 3,4,5-TMB with acetonitrile, then reduce the double bond. All that's left is the hoffman reaction. And I'll post that later. I'm sure it's been covered here before.
Have fun ^^