Quote: Originally posted by bbartlogpeople who aren't drug chemists are frustrated by their unavailability[/rquote  |
Story of my life.
“If Edison had a needle to find in a haystack, he would proceed at once with the diligence of the bee to examine straw after straw until he found
the object of his search.
I was a sorry witness of such doings, knowing that a little theory and calculation would have saved him ninety per cent of his labor.”
-Tesla
|
|
|
Sandmeyer
National Hazard
Posts: 784
Registered: 9-1-2005
Location: Internet
Member Is Offline
Mood: abbastanza bene
|
|
| Quote: Originally posted by azo |
You might get more of a responce if you provide more clearer information,or should i say if it was not about in this case phenylethylamines or
amphetamines it is not liked very mutch on this site ? |
What do you mean by "this site"? There are only a few members who have problems with the discussion of certain topics. If you want to speak about
cocaine, heroin or amphetamine you are free to do so loud and clear. As for the topic, there is one recent paper employing imidazole as catalyst:
EXPERIMENTAL
General Method for Henry Reaction in Aqueous Medium
A mixture of 2-nitrobenzaldehyde (1 mmol), nitromethane (3 mmol), and imidazole (0.25 mmol) was charged with 2 ml of distilled water. The
heterogeneous reaction mixture was stirred at ambient temperature and monitored by thin-layer chromatography (TLC). After completion of the reaction,
the product was extracted with 10 ml of diethyl ether. The organic layer was dried over anhydrous sodium sulfate and filtered. The organic filtrate
was evaporated under reduced pressure and dried under vacuum to give the crude product, which is reasonably pure (> 95% purity by 1H NMR) for
aromatic aldehydes. However, the residue was further purified by preparative TLC on silica gel to give the desired analytically pure products.
They try a variety of solvents (DCM, 1,4-Dioxane, Chloroform, THF, Acetonitrile, Methanol...) and get yields above 90% in all cases. See the article
for more details: DOI: 10.1080/00397910802045592
Synthetic Communications, Volume 38, Issue 18 January 2008, pages 3068 - 3073
|
|
|
Arrhenius
Hazard to Others
Posts: 282
Registered: 17-8-2008
Location: US & A
Member Is Offline
Mood: Stochastic
|
|
Hmm.. "...imidazole as a mild Lewis basic catalyst..." I think these authors are confused, seeing as how they drew the nitronate as an intermediate in
the reaction. I suppose catalytic aqueous base might also work based on pKa's. What do you think Sandmeyer, magic imidazole?
|
|
|
Sandmeyer
National Hazard
Posts: 784
Registered: 9-1-2005
Location: Internet
Member Is Offline
Mood: abbastanza bene
|
|
| Quote: Originally posted by Arrhenius | | Hmm.. "...imidazole as a mild Lewis basic catalyst..." I think these authors are confused, seeing as how they drew the nitronate as an intermediate in
the reaction. |
IMO that paper is a typical Indian synthetic communication  . They have these
cheesy introductions/discussions and often contain funny errors, but the practical methods have (at least in my experience) often worked as claimed
(or close to) and that's all I care about. I haven't tried this one though.
| Quote: | | I suppose catalytic aqueous base might also work based on pKa's. What do you think Sandmeyer, magic imidazole? |
There is a Chinese paper* from 2007 in which they describe the reaction carried out in water too. They use 30 mol % K2CO3 as a base together with I2
and KI [mmol ratio of aldehyde/nitromethane/I2/KI/K2CO3 being 1.0/5.0/0.3/0.3/0.3; H2O: 2 mL]. Interestingly, when no iodine is added they say that
the yield of nitroalcohol drops dramatically (from 95% to 20%). If we are to trust these papers I would conclude that we can't replace cat. imidazole
with cat. K2CO3 and get as high yields. I should add that I have no practical experience with nitroaldol reaction.
*Iodine Catalysis in Aqueous Medium: An Improved Reaction System for Knoevenagel and Nitroaldol Condensation.
Catalysis Letters (2007), 118, (1-2), 134-138.
Typical Procedure Condensation of p-Nitrobenzaldehyde with Nitromethane in Aqueous Media:
A solution of p-nitrobenzaldehyde (1 mmol) and nitromethane (5 mmol) was stirred at room temperature for 3 min, then an aqueous solution (2 mL) of KI
(0.3 mmol), K2CO3 (0.3 mmol) and I2 (0.3 mmol) was added and the mixture stirred for 2 h at room temperature. The mixture was treated with aqueous
Na2S2O3 (10%, 5 mL). Then the solution was extracted with Et2O (3 X 10 mL). The organic layer was dried and concentrated, and the crude product was
purified by column chromatography on silica gel (EtOAc:petroleum ether = 2:9) to afford 190 mg (90%) of pure product 2-Nitro-1-(4-nitrophenyl)ethanol.
m.p. 82�84 �C (Lit [16b].m.p. 83�85 �C);
There are literature examples of nitroaldol using bases such as alkali metal hydroxides, carbonates and alkoxides but practically most convenient
procedure is IMO to just mix aldehyde, nitromethane and 10% triethylamine as base, one such example is:
Preparation of the racemic nitroaldols:[24]
A mixture of benzaldehyde (1.0 mmol), MeNO2 (2.0 mmol), and Et3N (3 drops) in ethanol (2.0 mmoL) was stirred at room temperature for
10 h. Volatiles were removed in vacuo and the residue was purification by column chromatography on silica gel with elution with ethyl acetate/petrol
ether to afford the racemic nitroaldol adduct. yield of Ph-CH-OH-CH2-NO2 = 98%
Chemistry - A European Journal
Volume 13, Issue 6, Pages 1863-1871
doi: 10.1002/chem.200601220
emphasis mine...
|
|
|
Arrhenius
Hazard to Others
Posts: 282
Registered: 17-8-2008
Location: US & A
Member Is Offline
Mood: Stochastic
|
|
| Quote: | | There is a Chinese paper* from 2007 in which they describe the reaction carried out in water too. They use 30 mol % K2CO3 as a base together with I2
and KI |
I don't have a guess on a mechanism for this rate enhancement. Do you?
| Quote: | | IMO to just mix aldehyde, nitromethane and 10% triethylamine as base, one such example is: |
That's what I was taught. I think you can stop at the nitroalcohol if you simply don't heat it.
Given the org syn nitrostyrene prep (which I've done a couple times en route to 1-nitro-2-phenylcyclopropanes), I'm inclined to think any 'medium'
base (hydroxide, tertiary amine, pyridine), especially if homogeneous, will allow for the nitro aldol without subsequent condensation. As stated by
Barium:
| Quote: | | ...add acetic acid slowly to the aqueous solution of the nitronate while keeping the temp at 10-15 deg C. The oil that falls out is the nitroalcohol.
|
|
|
|
Sandmeyer
National Hazard
Posts: 784
Registered: 9-1-2005
Location: Internet
Member Is Offline
Mood: abbastanza bene
|
|
Iodine can act as a Lewis acid and activate the benzaldehyde carbonyl, indeed, it is sometimes used in Mukaiyama aldol for this purpose. I do not
understand why the Chinese scientists also put equimolar amount of KI (relative to I2), this means that I2 could exist in equilibrium with triiodide
ion but what is the point of this?
|
|
|
Ephoton
Hazard to Others
Posts: 463
Registered: 21-7-2005
Member Is Offline
Mood: trying to figure out why I need a dark room retreat when I live in a forest of wattle.
|
|
triethylamine
right isomer too that is if your a wolf in sheeps clothing
interesting sandmeyer I know they use the triiodide for aromatic iodination of phenols.
e3500 console login: root
bash-2.05#
|
|
|
azo
Hazard to Others
Posts: 163
Registered: 12-2-2008
Member Is Offline
Mood: No Mood
|
|
i think you need to no this arrhenius
If acidic protons are available (i.e. when R = H), the products tend to eliminate water to give nitroalkenes. Therefore, only small amounts of base
should be used if the isolation of the β-hydroxy nitro-compounds is desired.
or you do a dry media reaction with a microwave only takes several minutes for completion.
if you are a wolf in sheeps clothing
regards azo i
[Edited on 31-5-2010 by azo]
|
|
|
Arrhenius
Hazard to Others
Posts: 282
Registered: 17-8-2008
Location: US & A
Member Is Offline
Mood: Stochastic
|
|
| Quote: Originally posted by azo | If acidic protons are available (i.e. when R = H), the products tend to eliminate water to give nitroalkenes. Therefore, only small amounts of base
should be used if the isolation of the β-hydroxy nitro-compounds is desired.
[Edited on 31-5-2010 by azo] |
This is not true. Hydroxide is not a very good leaving group, and therefor under mild conditions (i.e. room temp or below) the reaction will not
proceed to eliminate water. The amount of base only effects the reaction velocity/velocities. Notice the Org Syn prep uses an excess of hydroxide as
the catalytic base, and even draws the second nitronate - the delocalized anion alpha to the nitro group - that would be ejecting hydroxide in the
condensation reaction! Only upon rapid acidification are they able to protonate the hydroxyl group and eject water,
a much better leaving group. As to the exact mechanism here, it may involve double protonation followed by loss of water.
Again: Org Syn - Nitrostyrene
[Edited on 31-5-2010 by Arrhenius]
|
|
|
Globey
Hazard to Others
Posts: 183
Registered: 9-2-2009
Member Is Offline
Mood: No Mood
|
|
i don't think all these compounds are necessarily all as unstable as infaously claimed. Just keep in topped off bottle, low light, room temp or cool,
etc...
|
|
|
amp
Harmless
Posts: 1
Registered: 3-8-2010
Member Is Offline
Mood: No Mood
|
|
Finding myself a bit confused regarding the stereochemistry here, particulary in relation to 4-methylaminorex..
So (1R,2S) & (1S,2R) PPA goes to trans-4MAR, but the (1R,2R) & (1S,2S) go to the oxazolidinone.
According to this, the reaction of EtNO2 with benzaldehyde using NaOH catalyst ala Kamlet gives ~35% (1R,2S) and the other ~65% (1S,2R).. But no (1R,2R) or
(1S,2S)? Therefore all of the PPA produced using Kamlet's method will afford trans-4MAR and no oxazolidinone? If this is the case then why worry about
using something like TEA to maximise (1R,2S) content?
| Quote: | | Phenylpropanolamine can also be manufactured by the reaction of benzaldehyde with nitroethane followed by catalytic reduction of the intermediate
nitro-alcohol, 2-nitro-1-phenyl-1-propanol. This process is described by Hoover et al., "Synthesis of 2-Amino-1-Phenyl-1-Propanol and Its Methylated
Derivatives," J. Org. Chem., Vol. 12, pp. 506-509 (1947), and has the advantage of almost no waste generation. The process, however, has a serious
disadvantage in that the nitro-alcohol intermediate, itself, is produced as an stereoisomeric mixture of (1R*,2S*)-2-nitro-1-phenyl-1-propanol and
(1S*,2R*)-2-nitro-1-phenyl-1-propanol having a low fraction of the desired (1R*,2S*)-2-nitro-1-phenyl-1-propanol stereoisomer. Upon reduction, the
fraction of the desired phenylpropanolamine stereoisomer, dl-norephedrine, is only about 30-35%, the remaining amount being the other stereoisomer,
dl-isonorephedrine. |
| Quote: | | Benzaldehyde (106.1 g., 1.0 mole) was agitated with sodium bisulfite (100.6 g., 1.06 mole) in 500 ml of water for 30 minutes. Separately, nitroethane
(82.5 g., 1.10 mole) was dissolved, with cooling, in a solution made from 50% sodium hydroxide (90.9 g., 1.13 mole) and 155 ml of water. This mixture
was added, over a period of 15 minutes, at 25°C, with vigorous agitation to the addition product of benzaldehyde and sodium bisulfite. After stirring
overnight, the lower layer was discarded. HPLC analysis of the upper layer showed a conversion of 125.4 g. (69.3%) of total
2-nitro-1-phenyl-1-propanol with a (1R*,2S*)-isomer content of 43.9 g. (35.1 %). |
But then, according to US Patent 5962737..
| Quote: | | It has been discovered that if a benzaldehyde derivative is reacted with a nitroalkane in the presence of a tertiary amine, the nitroalcohol formed is
of a threo configuration rather than a mixture of threo and erythro isomers which results when sodium hydroxide is used as the catalyst.
|
Which is somewhat contradictory. I'm thinking the reality is actually that TEA produces a mixture of the two desired isomers, and hydroxide affords
all four, but in what ratio? It is said above that ~35% is (1R,2S), but what about the rest if it's not all (1S,2R).. Anyone have some insight?
Struggling to find a definitive answer.
Also curious what the stereoisometry of Akabori-PPA is, 1:1:1:1 (1R,2S): (1S,2R): (1R,2R): (1S,2S)?
Cheers.
|
|
|
heksogen
Harmless
Posts: 25
Registered: 20-3-2004
Location: Poland
Member Is Offline
Mood: No Mood
|
|
Does anyone know any means of inhibiting dehydratation after Henry reaction? I am currently working on a total synthesis and using Henry reaction with
nitroethane I would save three bothersome steps. The aromatic aldehyde used is quite different from benzaldehydes, the product seems to be very prone
to dehydratation - RCHO/EtNO2/cat. Et3N or RCHO/EtNO2/cyclohexylamine at -22*C gives nitropropene only.
I am thinking of adding some transition metal complex, titanium maybe so that the nitroalcohol formed is complexed and sterricaly protected, then I
would destroy the complex in a two phase system. Something similar to soft enolization. Anyone tried such procedure?
Sorry for digging out a dinasour thread - still better than posting a new one.
[Edited on 24-7-2012 by heksogen]
|
|
|
DDTea
National Hazard
Posts: 940
Registered: 25-2-2003
Location: Freedomland
Member Is Offline
Mood: Degenerate
|
|
The Henry reaction is useful for so much more than amphetamines. It opens up a lot of doors from reagents readily available to the amateur.
Consider the Henry-Nef strategy. Starting from nitromethane, it is possible to synthesize a huge variety of asymmetric ketones using two sequential
nitroaldol reactions. Subsequent acid hydrolysis affords the ketone product (Nef reaction: http://en.wikipedia.org/wiki/Nef_reaction ).
Anyhow, the discussion about illicit substances and their syntheses may continue.
"In the end the proud scientist or philosopher who cannot be bothered to make his thought accessible has no choice but to retire to the heights in
which dwell the Great Misunderstood and the Great Ignored, there to rail in Olympic superiority at the folly of mankind." - Reginald Kapp.
|
|
|
Organicus
Harmless
Posts: 15
Registered: 29-5-2012
Member Is Offline
Mood: No Mood
|
|
http://www.erowid.org/archive/rhodium/chemistry/nitroalkene....
there's enough reading material in form of references..... took me <1min with google. so get your lazy ass up! u wont get spoon fed, especially on
this kinda topic.
BTW: i wouldnt try combining CH3NO2 with KOH or NaOH!
http://www.youtube.com/watch?v=r3CjogY5T0I&NR=1
http://www.youtube.com/watch?v=LdKrXH4PXqw&feature=watch...
nitronate salt deflagrating:
https://www.youtube.com/watch?v=iscHVlucDfI
BTW:
somethings wrong in this thread =)
some MOD, pls fix that!
[Edited on 25-7-2012 by Organicus]
|
|
|
heksogen
Harmless
Posts: 25
Registered: 20-3-2004
Location: Poland
Member Is Offline
Mood: No Mood
|
|
| Quote: |
there's enough reading material in form of references..... took me <1min with google. so get your lazy ass up! u wont get spoon fed, especially on
this kinda topic. BTW: i wouldnt try combining CH3NO2 with KOH or NaOH! |
I don't know how is that related to my post. If you took another <1min to read my message carefully, you'd know I'm not a drug chemist. I'm looking
for a reliable way to synthesize a nitroalcohol derived from a heterocyclic aldehyde. I didn't come across any publications on in situ complexation of
henry reaction products (searched via reaxys). It is more wise to ask than to do numerous experiments, maybe someone did it before. A lot can be found
on assymetric henry catalysed by shibasaki, evans or trost catalysts, but nothing on simple addition of transition metal. As soon as i try such
procedure I will post the results.
|
|
|
![[*]](images/xpblue/default_icon.gif){kind=icon}
