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shrent
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cool.gif posted on 15-2-2006 at 06:21
C=O to CH2 Reduction


I'm trying to reduce an amino acid derivative having C=O group to CH2.

I have references in which mostly it is being reduced by Pd/C. But is not being economical for me with this reagent.

Can I get your suggetions about this reduction with some economical process/reagents ?



Thanks in advance,

shrent
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[*] posted on 15-2-2006 at 12:26


Why is Pd/C not economical for you? Oke, you have to pay something when you buy it, but then you can use it 50times minimal..... VERY economical I would say.



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[*] posted on 15-2-2006 at 14:33


Could a variation of the Wolff-Kishner reaction work in this case? I don't usually see it with things like amino acids but it will remove carbonyl groups.



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[*] posted on 15-2-2006 at 15:43


If it's a carbonyl group on an amino acid you'll have to do more than Pd catalytic hydrogenation, might start with NaBH4/NiCl2 in water to reduce to the alcohol then use a two step to the hydrocarbon , that is halogenation and dehalogenation reduction....................solo

[Edited on 15-2-2006 by solo]




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[*] posted on 15-2-2006 at 21:55


After reducing it to an alcohol, acetylate and reduce, its easier than trying to reduce the alcohol. (I guess HI works)

[Edited on 16-2-2006 by enima]
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[*] posted on 15-2-2006 at 22:13


Dear friends,

First, Pd/C is really not economical for me with any sort as per the pricing calculations & recovery of catalyst/re-use.

Now doing reduction with these multiple steps, can't I use a single step process like wolff-kishner/clemmensen ?

Here, I'm also not sure about this W-K procedure, as my starting ester used in the amino acid derivative is an alpha-ketoester (ethyl-3-benzoylacrylate). (I made michael adduct of ethyl-3-benzoylacrylate & l-alanine) & I think, with this, W-K reduction might not work.

What do you say all ?
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[*] posted on 15-2-2006 at 22:28


Fermentation with yeast will reduce a carbonyl to an alcohol, or you could try the clemmensen reductio.



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[*] posted on 16-2-2006 at 12:44


Reference Information

ethyl-3-benzoylacrylate





[Edited on 16-2-2006 by solo]




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[*] posted on 17-2-2006 at 05:02
Reduction of Carbonyl Function to a Methyl Group


Solo posted this before:

Reduction of Carbonyl Function to a Methyl Group
Gan B. Bajracharya, Tsutomu Nogami, Tienan Jin, Kumiko Matsuda,a Vladimir Gevorgyan,
Yoshinori Yamamoto

Synthesis 2, 308, 2004

DOI:10.1055/s-2003-44356

Abstract: A direct exhaustive reduction of aliphatic carbonyl functions (aldehydes, acyl chlorides, esters and carboxylic acids) to a methyl group by triethylsilane (Et3SiH) in the presence of catalytic amount of tris(pentafluorophenyl)borane [B(C6F5)3] is described. Aromatic carbonyl functions could undergo partial reduction to the corresponding TES-protected benzylic alcohols.


:D




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[*] posted on 21-3-2006 at 02:27


I again clarify the reaction mechanism to easily understand my problem : Ethyl-3-benzoylacrylate + l-alanine making Michael adduct of both reactants as under :



Ph-C=O-CH=CH-COOC2H5

+

CH(CH3)-H2N COOH

to

Ph-C=O-CH2-CH(COOC2H5)-NH-CH(CH3)-COOH




Now, how can I reduce this adduct to get my final product :

Ph-CH2-CH2-CH(COOC2H5)-NH-CH(CH3)-COOH

i.e. : getting C=O to CH2.


PLS ANYONE KNOWS ABOUT THIS, COMMENT & SUGGEST.
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[*] posted on 24-3-2006 at 11:01


Wolff-Kischner reaction will work for sure.

Try : NaOH, hydrazine and diethylene glycol.

You make the hydrazone on your carbonyl in basic catalysis. Then you do the reaction with the diethylene glycol.
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[*] posted on 28-3-2006 at 04:33


You may be right, but my compound (adduct) is unstable in alkaline media converting the less desired R,S diastereomer of the adduct from S,S. (My michael adduct is a diastereomer compound having mostly the S,S & less R,S configuration).

Hence, I can not use this method.

What do you think about clemmensen method ?

By the way, both of these methods may work for such amino acid compounds ?


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[Edited on 28-3-2006 by shrent]
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[*] posted on 28-3-2006 at 04:50


A. Reactions Involving Replacement of Oxygen by Hydrogen
In reactions 19-33-19-37, a C=O group is reduced to a CH2 group.
19-33 Reduction of Carbonyl to Methylene in Aldehydes and Ketones
DlHYDRODE-OXOBISUBSTITUTION
Zn-Hg
R-fTR' ~ ^ r ^ R-CH*-R'
o
There are various ways of reducing the C=O group of aldehydes and ketones to
CH2.512 The two oldest, but still very popular, methods are the Clemmensen
reduction512 and the Wolff-Kishner reduction. The Clemmensen reduction consists
of heating the aldehyde or ketone with zinc amalgam and aqueous HO.514 Ketones
are reduced more often than aldehydes. In the Wolff-Kishner reduction,515 the
aldehyde or ketone is heated with hydrazine hydrate and a base (usually NaOH or
KOH). The Huang-Minion modification516 of the Wolff-Kishner reaction, in which
the reaction is carried out in refluxing diethylene glycol, has completely replaced the
original procedure. The reaction can also be carried out under more moderate
conditions (room temperature) in DMSO with potassium tert-butoxide as base.517
The Wolff-Kishner reaction can also be applied to the semicarbazones of aldehydes
or ketones. The Clemmensen reduction is usually easier to perform, but it fails for
acid-sensitive and high molecular weight substrates. For these cases, the Wolff-
Kishner reduction is quite useful. For high molecular weight substrates, a modified
Clemmensen reduction, using activated zinc and gaseous HC1 in an organic solvent
such as ether or acetic anhydride, has proved successful.518 The Clemmensen and
Wolff-Kishner reactions are complementary, since the former uses acidic and the
latter basic conditions.
Both methods are fairly specific for aldehydes and ketones and can be carried out
with many other functional groups present. However, certain types of aldehydes and
ketones do not give normal reduction products. Under Clemmensen conditions,519
7-hydroxy ketones give either ketones (hydrogenolysis of the OH, 10-81) or alkenes,
and 1,3-diones usually undergo rearrangement, (e.g., MeCOCH2COMe —> MeCO
CHMe2.520 Neither method is suitable for oc,p-unsaturated ketones. These give
pyrazolines521 under Wolff-Kishner conditions, while under Clemmensen conditions
both groups of these molecules may be reduced or if only one group is reduced,
it is the C=C bond.522 Sterically hindered ketones are resistant to both the Clemmensen
and Huang-Minion procedures but can be reduced by vigorous treatment
with anhydrous hydrazine.523 In the Clemmensen reduction, pinacols (19-55) are
often side products.
Other reagents have also been used to reduce the C=O of aldehydes and ketones
to CH2.524 Among these are Me3SiCl followed by Et3SiH/TiCl4,525 Ni(OAc)2 on
1548 OXIDATIONS AND REDUCTIONS
borohydride exchange resin, Et3SiH on pyridinium poly(hydrogen fluoride)
527 Labbreveated as PPHF], ' and, for aryl ketones (ArCOR and ArCOAr),
NaBH4-F3CCOOH,528 NaBH4-AlCl3,529 HCOONH4-Pd-C,530 or trialkylsilanes
in F3CCOOH. Most of these reagents also reduce aryl aldehydes ArCHO to
532 methylbenzenes ArCH3. Aliphatic aldehydes RCHO can be reduced to RCH3
with titanocene dichloride, (C5H5)2TiCl2.533 One carbonyl group of 1,2-diketones
can be selectively reduced by H2S with an amine catalyst or by HI in refluxing
acetic acid.535 One carbonyl group of quinones can be reduced with copper and
sulfuric acid or with tin and HC1:536
One carbonyl group of 1,3-diketones was selectively reduced by catalytic hydrogenolysis.
537
The carbonyl of acid derivatives can be reduced in some cases. Lactones are
converted to cyclic ethers by treatment with Cp2TiCl2 followed by Et3SiH on
Amberlyst 15®.538
An indirect method of accomplishing the reaction is reduction of tosylhydrazones
(R2C=N-NHTs) to R2CH2 with NaBH4, BH3, catecholborane, bis(benzyloxy)-
borane, or NaBH3CN. The reduction of a,(3-unsaturated tosylhydrazones with
NaBH3CN, with NaBH4—HOAc, or with catecholborane proceeds with migration of
the double bond to the position formerly occupied by the carbonyl carbon, even if
this removes the double bond from conjugation with an aromatic ring,539 for
example,
CH=CH-c-CH3
11
N-NH-Ts
CH2-CH=CH-CH3
A cyclic mechanism is apparently involved:
R2 R3
R1—C=C-C-R4
N-NHTs
R1 V\ ^ '"
N=N R4
R2 R3
R1 —CH-C=CHR4 + N?
Another indirect method is conversion of the aldehyde or ketone to a dithioacetal or
ketal, and desulfurization of this (14-34).
It is interesting to see that amines can be deaminated to give the corresponding
methylene compounds with low-valent titanium (TiCl3/Li/THF).540
The first step in the mechanism541 of the Wolff-Kishner reaction consists of
formation of the hydrazone (16-19).
R2C=O R2C=N-NH2
CHAPTER 19 REACTIONS 1549
It is this species that undergoes reduction in the presence of base, most likely in the
following manner:
OH~
R2C=H-NH2 -*=^ R2CH-N=NH + OH~ - R2CH-N=N~ + H2O
- N , = H2O
R2CH-N=N" - R2CH *- R2CH2 + OH~
Not much is known about the mechanism of the Clemmensen reduction. Several
mechanisms have been proposed,542 including one going through a zinc-carbene
intermediate.543 One thing reasonably certain is that the corresponding alcohol is not
an intermediate, since alcohols prepared in other ways fail to give the reaction. Note
that the alcohol is not an intermediate in the Wolff-Kishner reduction either.
OS I, 60; II, 62, 499; III, 410, 444, 513, 786; IV, 203, 510; V, 533, 747; VI, 62,
293, 919; VII, 393. Also see OS IV, 218; VII, 18.


...................for the full picture and diaghrams see March's 5th edition page 1547




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[*] posted on 29-3-2006 at 06:23


Did you try this method ; convert the ketone into a thioacetal with a dithiol then reduction with raney nickel?
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[*] posted on 29-3-2006 at 08:35


No dear ! I don't have this method.

Can you give me some experimental ref. for this ?
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[*] posted on 29-3-2006 at 16:32


I just learned this reduction of a carbonyl a month ago in my organic course. I don't have any experimental reference.

React your carbonyl with a thiol to form the thioacetal. Then this product is reacted with Raney Nickel in a EtOH environment with heating.

Look at this document page 11-13
There's 3 way of reducting a carbonyl
Sorry it's in french but it's mostly visual format.

Attachment: carbonyles(3).pdf (448kB)
This file has been downloaded 1173 times

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[*] posted on 6-4-2006 at 08:45


Thanks new-b !

I'm finding now route for making thioacetal.

If anyone have this, pls post for me.

But I'm still looking for some other solution for my reduction. Therefore I had attached link for the reference patent file for developing my molecule.

The reduction here is done with Pd/C with H2 (SEE EXAMPLE 12 & 13), but it is not being economical at all & I want to replace this catalyst with some other method.

PATENT LINK : http://v3.espacenet.com/textdes?DB=EPODOC&IDX=US4925969&F=0&QPN=US4925969

If you want the above file in pdf, then in the above page, click on "Original document".



[Edited on 6-4-2006 by shrent]
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[*] posted on 6-4-2006 at 17:53


Generally, thioacetals are made in a similar way to acetals, but using a thiol along with an aldehyde or ketone, and a Lewis acid catalyst rather than an acid catalyst.



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thumbup.gif posted on 18-4-2006 at 02:44
Some other possibility


Here, I also think if some other possibility is there to get CH2 from C=O in my final molecule.

Is it possible to only reduce the C=O of my starting material, Ethyl-3-benzoylacrylate : Ph-C=O-CH=CH-COOC2H5 & not affecting the other bonds (CH=CH) & groups present therein ?

Pls comment..............
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[*] posted on 26-4-2006 at 16:30


Quote:

What do you think about clemmensen method ?

Bearing in mind that I haven't used either the Clemmensen or the Wolff-Kishner reaction, it seems that it depends on your substrate:
Quote:

The substrate must be stable in the strongly acidic conditions of the Clemmensen reduction. Acid sensitive substrates should use the Wolff-Kishner reduction, which utilizes strongly basic conditions.

Source. Safety is another consideration; W-K is probably more dangerous to the chemist (hydrazine is really nasty stuff) but the Clemmensen is probably more dangerous to the environment (and possibly to consumers, if the intended product is something that is taken internally). I imagine the environmental aspect of this could be managed if you have a way of dealing with the mercury (ideally recycling it).

[Edited on 27-4-2006 by nitroglycol]
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