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All 13 posts Subject: MDA via Hoffmann Reaction Please login to post Down

Rhodium
(Chief Bee)
03-17-04 23:22
No 495809
User Picture       MDA via Hoffmann Reaction
(Rated as: excellent)

1-Pyridylisoquinolines
D.H. Hey and J.M. Williams
J. Chem. Soc. 1527-1532 (1951) (https://www.rhodium.ws/pdf/mda.hoffman-rxn.pdf)

1-(3,4-Methylenedioxyphenyl)-2-propylamine (MDA)

alpha-Piperonylpropionic acid (27g.; [Post 497275 (Rhodium: "Ber. 13, 756-761 (1880)", Novel Discourse)]) was treated with an excess of phosphorus trichloride and after the vigorous reaction had subsided the mixture was heated to 60°C for 2 hours. The excess of phosphorus trichloride was distilled from the mixture under reduced pressure. and the acid chloride extracted from the residue with dry ether and added with shaking to aqueous ammonia (d. 0.88) in large excess. The mixture was heated on a water-bath to remove the ether and then chilled. The amide (26 g) was filtered off from the solution. A sample separated from aqueous alcohol in plates, mp 121°C. A cold solution of alkaline sodium hypochlorite was prepared by absorbing chlorine (5.5 g) in a solution of sodium hydroxide (20 g) in water (50 mL) and crushed ice (100 g). To this mechanically stirred solution was added the above powdered crude amide (25.5 g). After 10 minutes the temperature was slowly raised to 50°C and a solution of potassium hydroxide (36 g) in water (200 mL) was slowly added. When all the amide had dissolved the mixture was again heated to 70°C and kept at 70-80°C for half an hour. during which an oil commenced to separate from the solution. The mixture was cooled and extracted with benzene. After removal of benzene from the dried (K₂CO₃) extract, the residue was distilled under reduced pressure to give 1-(3,4-methylenedioxyphenyl)-2-propylamine (9.5g, bp 149-150°C/14mmHg).
Merck (Patent DE274350) describes the preparation of this amine by the addition of hydrogen bromide to safrole followed by amination, and records bp 153°C/19 mmHg.

^{The Hive - Clandestine Chemists Without Borders}

Rhodium
(Chief Bee)
03-25-04 15:56
No 497275
User Picture       Ber. 13, 756-761 (1880)
(Rated as: good read)

Ueber Methylenkaffeesäure, Methylenhomokaffeesäure und die daraus durch Anlagerung von Wasserstoff entstehenden säuren
C. Lorenz
Chem. Ber. 13, 756-761 (1880) (https://www.rhodium.ws/pdf/lorenz1880.pdf)

Experimental

3,4-Methylenedioxycinnamic acid

A mixture of piperonal (5g), sodium acetate (3g) and acetic anhydride (6g) was boiled under reflux for six hours, and upon cooling the reaction mixture to room temp the flask contents solidified to a brown cake. The cake was softened by stirring it in hot water, and after cooling it was extracted with ether. The pooled etheral extracts were in turn extracted with aqueous sodium carbonate, and slow acidification of the pooled aqueous extracts with aqueous hydrochloric acid gave the title product as a white flocculent precipitate. The acid is insoluble in water, easily soluble in ether and ethanol and could be recrystallized in 25% aqueous ethanol after decolorization with activated charcoal. Thus the product could be isolated as white microcrystalline powder, with a melting point of 232°C.

3,4-Methylenedioxyhydrocinnamic acid

3,4-Methylenedioxycinnamic acid is covered with water and an excess of 3% sodium amalgam is added (125g per gram of acid) and it is reacted first at room temperature, then with mild heating, until the solution becomes colorless. The now basic solution is decanted from the mercury and made slightly acid with aqueous sulfuric acid, filtered to remove impurities and then extracted with ether. Upon evaporation of the pooled etheral extracts, the acid formed large colorless crystals. Upon recrystallization from water, to which a little ethanol was added, the acid crystallized in long colorless needles, mp 84°C.

alpha-Methyl-3,4-Methylenedioxycinnamic acid

This was prepared exactly like the above cinnamic acid, using identical amounts of reagents, but using propionic anhydride instead of acetic anhydride. The acid is insoluble in water, soluble in alcohol and ether, and upon recrystallization from dilute ethanol it formed small colorless prisms, mp 192-194°C.

alpha-Methyl-3,4-Methylenedioxyhydrocinnamic acid

The Na/Hg reduction was performed exactly like above. The acid is less water soluble than 3,4-Methylenedioxyhydrocinnamic acid, and unless too dilute, it could be precipitated from the basic aqueous solution by addition of mineral acids. Easily soluble in alcohol and ether. Upon recrystallization from dilute ethanol it formed thick yellowish prisms, mp 77°C.

^{The Hive - Clandestine Chemists Without Borders}

josef_k
(Hive Bee)
03-25-04 19:25
No 497316
      I've been thinking on the subject of ...

I've been thinking on the subject of alpha-methylphenylpropionic acid. Could you possible alkylate propionitrile with a benzylchloride and NaOH/PTC, gently hydrolize to the amide and then do the hoffman on it? Or is it only phenylacetonitriles that are possible to alkylate that way?

Rhodium
(Chief Bee)
03-25-04 20:09
No 497329
User Picture       Aliphatic nitriles are not as reactive

It only works satisfactorily with arylacetonitriles or nitriles with an electron-withdrawing group in the beta position. To deprotonate a simple aliphatic nitrile you would need to use superbases like BuLi or LDA.

^{The Hive - Clandestine Chemists Without Borders}

Rhodium
(Chief Bee)
04-12-04 04:24
No 500302
User Picture       alpha-methyl-3,4-methylenedioxycinnamic acid
(Rated as: good read)

3-Methyl-3,4-dihydroisoquinolines and 3-Methyl-1,2,3,4-tetrahydroisoquinolines
Walter S. Ide, Johannes S. Buck
J. Am. Chem. Soc. 62, 425-428 (1940) (https://www.rhodium.ws/pdf/alpha-methyl-md-cinnamic.pdf)
____ ___ __ _

Some α-Alkylcinnamic Acids and Their Derivatives
Bogert, M. T. and Davidson, D.
J. Am. Chem. Soc. 54, 334-338 (1932) (https://www.rhodium.ws/pdf/alpha-alkyl-cinnamic.pdf)

^{The Hive - Clandestine Chemists Without Borders}

ning
(acetaminophanatic)
04-17-04 17:16
No 501312
User Picture       You can alkylate propionitrile with benzaldehyde

And acetonitrile, using ptc, or, I think, alumina also. I have some papers on this. But you still have to reduce the double bond. Damn. laugh

Then again, I think if you do the hoffmann rearrangement on an alpha-unsaturated amide, it turns into a ketone or aldehyde, which could bee useful by itself.

Why is it so much harder to alkylate things with halides than with aldehydes? Is it because the aldehydes have stable transition states?

I've been chased by both cops and robbers. So what does that make me?

Rhodium
(Chief Bee)
04-17-04 21:53
No 501374
User Picture       Non Sequitur

Why is it so much harder to alkylate things with halides than with aldehydes?

That question doesn't make sense to me - phenols are for example way easier to alkylate with alkyl halides than with aldehydes... You need to specify the reactants and reaction conditions to be able to state such a thing.

^{The Hive - Clandestine Chemists Without Borders}

ning
(acetaminophanatic)
04-19-04 21:26
No 501655
User Picture       I mean deprotonateable things

Things with acidic hydrogens, to make a C-C bond. Like R-X + MeNO2 --> R-CH2-NO2, versus R-CHO + MeNO2 --> R-CH=CH-NO2...
It seems that it is always easier for the aldol or "dehydrative" coupling than for the alkylative/SN-2 displacement coupling. Hm. Know what I mean? My chem speak still isn't so good ^^

I've been chased by both cops and robbers. So what does that make me?

ning
(acetaminophanatic)
04-19-04 22:05
No 501661
User Picture       OK, here we go....

This'll bee another megapost, I'm afraid.

Org syn CV 7, 108
http://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, 1882
3,4-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, 4640
Ok, 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.

-------
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 ^^

I've been chased by both cops and robbers. So what does that make me?

Nicodem
(Hive Bee)
04-19-04 23:18
No 501674
User Picture       Ning, in the first example you ask about (R-X...

Ning, in the first example you ask about (R-X + MeNO2 --> R-CH2-NO2, versus R-CHO + MeNO2 --> R-CH=CH-NO2) the aldol condensation is successful because there is no problem with the O-alkylation of the nitro group. The adduct of such a O-alkylation (R-CH(OH)-O-NO=CH2) is instable and the reaction is reversible while the product of the C-alkylation (R-CH(OH)-CH2-NO2) is much more stable.
I hope you are satisfied with this explanation. The other examples you cited are again highly specific and require a specific explanation.

“The real drug-problem is that we need more and better drugs.” – J. Ott

Rhodium
(Chief Bee)
04-26-04 18:58
No 503166
User Picture       CTH reduction of cinnamic acid double bond

Post 400079 (Rhodium: "Aqueous PdCl2 CTH cinnamic acid hydrogenation", Novel Discourse)

^{The Hive - Clandestine Chemists Without Borders}

ning
(acetaminophanatic)
04-27-04 03:52
No 503252
User Picture       Oh dear...

I'm sorry....actually, I should have said "R-X + R-CH2-CN" vs. "R=O + R-CH2-CN"... I remember you spent a lot of time explaining about the bidentate nature of nitro compounds to me before... tongue Please don't bee exasperated ^^

See, I searched the beilstein, etc. for reactions involving alkylation of various acidic methyl(ene)s, activated by (for example) -CN, -COOR, -NO2, etc. and it turned out that alkylations involving halide displacement seem to bee much harder, need really strong bases, etc, for all of the above groups, while carbonyls could bee induced to condense with only NaOH or alumina. And I couldn't understand why that was. So, yes, I realize the special problem plaguing those annoying nitro compounds, but what about the others?

I've been chased by both cops and robbers. So what does that make me?

Rhodium
(Chief Bee)
04-27-04 06:45
No 503273
User Picture       Terminology complaint

http://www.hyperdictionary.com/search.aspx?define=bidentate

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	All 13 posts		Subject: MDA via Hoffmann Reaction		Please login to post		Down


		Rhodium (Chief Bee) 03-17-04 23:22 No 495809				MDA via Hoffmann Reaction (Rated as: excellent)
						1-Pyridylisoquinolines D.H. Hey and J.M. Williams J. Chem. Soc. 1527-1532 (1951) (https://www.rhodium.ws/pdf/mda.hoffman-rxn.pdf) 1-(3,4-Methylenedioxyphenyl)-2-propylamine (MDA) alpha-Piperonylpropionic acid (27g.; *[Post 497275 (Rhodium: "Ber. 13, 756-761 (1880)", Novel Discourse)])* was treated with an excess of phosphorus trichloride and after the vigorous reaction had subsided the mixture was heated to 60°C for 2 hours. The excess of phosphorus trichloride was distilled from the mixture under reduced pressure. and the acid chloride extracted from the residue with dry ether and added with shaking to aqueous ammonia (d. 0.88) in large excess. The mixture was heated on a water-bath to remove the ether and then chilled. The amide (26 g) was filtered off from the solution. A sample separated from aqueous alcohol in plates, mp 121°C. A cold solution of alkaline sodium hypochlorite was prepared by absorbing chlorine (5.5 g) in a solution of sodium hydroxide (20 g) in water (50 mL) and crushed ice (100 g). To this mechanically stirred solution was added the above powdered crude amide (25.5 g). After 10 minutes the temperature was slowly raised to 50°C and a solution of potassium hydroxide (36 g) in water (200 mL) was slowly added. When all the amide had dissolved the mixture was again heated to 70°C and kept at 70-80°C for half an hour. during which an oil commenced to separate from the solution. The mixture was cooled and extracted with benzene. After removal of benzene from the dried (K₂CO₃) extract, the residue was distilled under reduced pressure to give 1-(3,4-methylenedioxyphenyl)-2-propylamine (9.5g, bp 149-150°C/14mmHg). Merck (Patent DE274350) describes the preparation of this amine by the addition of hydrogen bromide to safrole followed by amination, and records bp 153°C/19 mmHg. ^{The Hive - Clandestine Chemists Without Borders}



		Rhodium (Chief Bee) 03-25-04 15:56 No 497275				Ber. 13, 756-761 (1880) (Rated as: good read)
						Ueber Methylenkaffeesäure, Methylenhomokaffeesäure und die daraus durch Anlagerung von Wasserstoff entstehenden säuren C. Lorenz Chem. Ber. 13, 756-761 (1880) (https://www.rhodium.ws/pdf/lorenz1880.pdf) Experimental 3,4-Methylenedioxycinnamic acid A mixture of piperonal (5g), sodium acetate (3g) and acetic anhydride (6g) was boiled under reflux for six hours, and upon cooling the reaction mixture to room temp the flask contents solidified to a brown cake. The cake was softened by stirring it in hot water, and after cooling it was extracted with ether. The pooled etheral extracts were in turn extracted with aqueous sodium carbonate, and slow acidification of the pooled aqueous extracts with aqueous hydrochloric acid gave the title product as a white flocculent precipitate. The acid is insoluble in water, easily soluble in ether and ethanol and could be recrystallized in 25% aqueous ethanol after decolorization with activated charcoal. Thus the product could be isolated as white microcrystalline powder, with a melting point of 232°C. 3,4-Methylenedioxyhydrocinnamic acid 3,4-Methylenedioxycinnamic acid is covered with water and an excess of 3% sodium amalgam is added (125g per gram of acid) and it is reacted first at room temperature, then with mild heating, until the solution becomes colorless. The now basic solution is decanted from the mercury and made slightly acid with aqueous sulfuric acid, filtered to remove impurities and then extracted with ether. Upon evaporation of the pooled etheral extracts, the acid formed large colorless crystals. Upon recrystallization from water, to which a little ethanol was added, the acid crystallized in long colorless needles, mp 84°C. alpha-Methyl-3,4-Methylenedioxycinnamic acid This was prepared exactly like the above cinnamic acid, using identical amounts of reagents, but using propionic anhydride instead of acetic anhydride. The acid is insoluble in water, soluble in alcohol and ether, and upon recrystallization from dilute ethanol it formed small colorless prisms, mp 192-194°C. alpha-Methyl-3,4-Methylenedioxyhydrocinnamic acid The Na/Hg reduction was performed exactly like above. The acid is less water soluble than 3,4-Methylenedioxyhydrocinnamic acid, and unless too dilute, it could be precipitated from the basic aqueous solution by addition of mineral acids. Easily soluble in alcohol and ether. Upon recrystallization from dilute ethanol it formed thick yellowish prisms, mp 77°C. ^{The Hive - Clandestine Chemists Without Borders}



		josef_k (Hive Bee) 03-25-04 19:25 No 497316				I've been thinking on the subject of ...
						I've been thinking on the subject of alpha-methylphenylpropionic acid. Could you possible alkylate propionitrile with a benzylchloride and NaOH/PTC, gently hydrolize to the amide and then do the hoffman on it? Or is it only phenylacetonitriles that are possible to alkylate that way?



		Rhodium (Chief Bee) 03-25-04 20:09 No 497329				Aliphatic nitriles are not as reactive
						It only works satisfactorily with arylacetonitriles or nitriles with an electron-withdrawing group in the beta position. To deprotonate a simple aliphatic nitrile you would need to use superbases like BuLi or LDA. ^{The Hive - Clandestine Chemists Without Borders}



		Rhodium (Chief Bee) 04-12-04 04:24 No 500302				alpha-methyl-3,4-methylenedioxycinnamic acid (Rated as: good read)
						3-Methyl-3,4-dihydroisoquinolines and 3-Methyl-1,2,3,4-tetrahydroisoquinolines Walter S. Ide, Johannes S. Buck J. Am. Chem. Soc. 62, 425-428 (1940) (https://www.rhodium.ws/pdf/alpha-methyl-md-cinnamic.pdf) ____ ___ __ _ Some α-Alkylcinnamic Acids and Their Derivatives Bogert, M. T. and Davidson, D. J. Am. Chem. Soc. 54, 334-338 (1932) (https://www.rhodium.ws/pdf/alpha-alkyl-cinnamic.pdf) ^{The Hive - Clandestine Chemists Without Borders}



		ning (acetaminophanatic) 04-17-04 17:16 No 501312				You can alkylate propionitrile with benzaldehyde
						And acetonitrile, using ptc, or, I think, alumina also. I have some papers on this. But you still have to reduce the double bond. Damn. Then again, I think if you do the hoffmann rearrangement on an alpha-unsaturated amide, it turns into a ketone or aldehyde, which could bee useful by itself. Why is it so much harder to alkylate things with halides than with aldehydes? Is it because the aldehydes have stable transition states? I've been chased by both cops and robbers. So what does that make me?



		Rhodium (Chief Bee) 04-17-04 21:53 No 501374				Non Sequitur
						Why is it so much harder to alkylate things with halides than with aldehydes? That question doesn't make sense to me - phenols are for example way easier to alkylate with alkyl halides than with aldehydes... You need to specify the reactants and reaction conditions to be able to state such a thing. ^{The Hive - Clandestine Chemists Without Borders}



		ning (acetaminophanatic) 04-19-04 21:26 No 501655				I mean deprotonateable things
						Things with acidic hydrogens, to make a C-C bond. Like R-X + MeNO2 --> R-CH2-NO2, versus R-CHO + MeNO2 --> R-CH=CH-NO2... It seems that it is always easier for the aldol or "dehydrative" coupling than for the alkylative/SN-2 displacement coupling. Hm. Know what I mean? My chem speak still isn't so good ^^ I've been chased by both cops and robbers. So what does that make me?



		ning (acetaminophanatic) 04-19-04 22:05 No 501661				OK, here we go....
						This'll bee another megapost, I'm afraid. Org syn CV 7, 108 http://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, 1882 3,4-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, 4640 Ok, 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. ------- 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 ^^ I've been chased by both cops and robbers. So what does that make me?



		Nicodem (Hive Bee) 04-19-04 23:18 No 501674				Ning, in the first example you ask about (R-X...
						Ning, in the first example you ask about (R-X + MeNO2 --> R-CH2-NO2, versus R-CHO + MeNO2 --> R-CH=CH-NO2) the aldol condensation is successful because there is no problem with the O-alkylation of the nitro group. The adduct of such a O-alkylation (R-CH(OH)-O-NO=CH2) is instable and the reaction is reversible while the product of the C-alkylation (R-CH(OH)-CH2-NO2) is much more stable. I hope you are satisfied with this explanation. The other examples you cited are again highly specific and require a specific explanation. “The real drug-problem is that we need more and better drugs.” – J. Ott



		Rhodium (Chief Bee) 04-26-04 18:58 No 503166				CTH reduction of cinnamic acid double bond
						Post 400079 (Rhodium: "Aqueous PdCl2 CTH cinnamic acid hydrogenation", Novel Discourse) ^{The Hive - Clandestine Chemists Without Borders}



		ning (acetaminophanatic) 04-27-04 03:52 No 503252				Oh dear...
						I'm sorry....actually, I should have said "R-X + R-CH2-CN" vs. "R=O + R-CH2-CN"... I remember you spent a lot of time explaining about the bidentate nature of nitro compounds to me before... Please don't bee exasperated ^^ See, I searched the beilstein, etc. for reactions involving alkylation of various acidic methyl(ene)s, activated by (for example) -CN, -COOR, -NO2, etc. and it turned out that alkylations involving halide displacement seem to bee much harder, need really strong bases, etc, for all of the above groups, while carbonyls could bee induced to condense with only NaOH or alumina. And I couldn't understand why that was. So, yes, I realize the special problem plaguing those annoying nitro compounds, but what about the others? I've been chased by both cops and robbers. So what does that make me?



		Rhodium (Chief Bee) 04-27-04 06:45 No 503273				Terminology complaint
						http://www.hyperdictionary.com/search.aspx?define=bidentate ^{The Hive - Clandestine Chemists Without Borders}

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