Author Topic: Catalytic Transfer Hydrogenation: A review  (Read 368 times)

akcom

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Catalytic Transfer Hydrogenation: A review
« on: April 03, 2011, 04:21:12 PM »
This is really the way to go folks.  The bees knees as it were.  The catalyst is relatively cheap, the procedure is mild, and the work up is a breeze.  I've included a review on CTH reductions (with coverage on imines) for those that are interested.  I'd really like to see some experiments with these techniques here.  I'm more than willing to the get the ball rolling, so expect some results in the upcoming weeks!
« Last Edit: April 03, 2011, 04:23:04 PM by akcom »

akcom

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Re: Catalytic Transfer Hydrogenation: A review
« Reply #1 on: April 04, 2011, 12:45:30 AM »
This review is more recent and much more in depth.  Enjoy!

Interestingly, they may have discovered why homemade catalyst seems to be less active than commercial catalyst, which was noted several times at the hive:
Quote
For example, the finely divided metals Ru,
Rh, Pd,  and Pt were inactive for the  dehydrogenation
of  benzhydrol  but  all of  these metals when sup-
ported on charcoal effected its dehydrogenation.
It was found that  commercially available catalysts supported
on charcoal contained small quantities of  chloride ions
which were responsible for their good activity; hetero-
geneous catalysts prepared by hydrogenation  of  chlo-
ride-free metal oxides were inactive

atara

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Re: Catalytic Transfer Hydrogenation: A review
« Reply #2 on: April 04, 2011, 01:38:29 AM »
Chloride, huh? Looks like it might be a good idea to put some chloride source into most reactions of this nature. And that's awesome work you've got there.

akcom

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Re: Catalytic Transfer Hydrogenation: A review
« Reply #3 on: April 04, 2011, 03:07:01 AM »
I've found a couple refs that should imines should be reduced via Zn/HCOOH just as most other groups are.  This could be an awesome workup.
They use oximes here, but THIS was referenced in a pubmed article where the reduction was of a benzimine
Quote
A solution of triarylethanone 3 (0.90 mmol)
and hydroxylamine hydrochloride (5.4 mmol) in dry pyridine
(18 mL) was refluxed for 2-2.5 h. The reaction mixture was
allowed to cool to room temperature and evaporated to dryness
in vacuo, and the residue was partitioned between water (10
mL) and CH2Cl2 (10 mL). The organic extract was washed with
water (2  10 mL), and the aqueous layer was extracted with
CH2Cl2 (2  10 mL). The combined organic extracts were dried
over anhydrous sodium sulfate and evaporated in vacuo.
Without performing further purification, the resulting mixture
was dissolved in the smallest amount of THF, 70% aqueous
formic acid (17 mL) was added, and zinc powder (26.7 mmol)
was added portionwise over 30 min after cooling the solution
with an ice bath. The reaction mixture was stirred for 17-19
h at room temperature, filtered on sand, and washed with
EtOAc. The filtrate was neutralized with a concentrated
ammonia solution to pH 8 and then extracted with EtOAc (3
 30 mL). The organic phase was washed with water (50 mL),
dried over anhydrous sodium sulfate, and evaporated in vacuo
to give a residue that was purified by flash chromatography
on silicagel using 10-40% EtOAc/CH2Cl2 or 2-5% MeOH/
CH2Cl2 as the eluent.

akcom

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Re: Catalytic Transfer Hydrogenation: A review
« Reply #4 on: April 04, 2011, 05:14:07 AM »
Is anyone here familiar with group X CTH utilizing 2-propanol?  I've only been able to find sparse references for their use in imine reduction.  Seems the ligands have to be designed to increase the energy of less desirable side reactions.

jon

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Re: Catalytic Transfer Hydrogenation: A review
« Reply #5 on: April 04, 2011, 06:27:00 AM »

akcom

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Re: Catalytic Transfer Hydrogenation: A review
« Reply #6 on: April 04, 2011, 07:28:13 AM »
jon, I'd like to avoid Al alkoxide compounds.  I haven't really looked into their synthesis, but I don't think they'd be easy to obtain?

Rh/Ir compounds while perhaps more expensive are pretty easy to obtain and a lot of the times the metal+ligand complex is commercially available.

Anyway, this looks interesting: http://www.sigmaaldrich.com/chemistry/chemical-synthesis/technology-spotlights/chiral-phosphoric.html
Organocatalytic transfer hydrogenation.

akcom

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Re: Catalytic Transfer Hydrogenation: A review
« Reply #7 on: April 04, 2011, 07:40:30 AM »
Here's a reductive amination using Rh binap catalyst in a leukart type reaction. amazing yields

atara

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Re: Catalytic Transfer Hydrogenation: A review
« Reply #8 on: April 04, 2011, 09:00:49 AM »
jon, I'd like to avoid Al alkoxide compounds.  I haven't really looked into their synthesis, but I don't think they'd be easy to obtain?

Aluminium amalgam + dry isopropanol is basically all it is. Only issue is (I think) you've got to prepare your imine before adding the aluminium alkoxide, plus the fact that mercury sucks.

jon

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Re: Catalytic Transfer Hydrogenation: A review
« Reply #9 on: April 04, 2011, 10:22:32 AM »
no i don't even think that reduction is for imines it's for ketones and such.
a chemoselective reduction if you will.

akcom

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Re: Catalytic Transfer Hydrogenation: A review
« Reply #10 on: April 10, 2011, 02:48:38 AM »
Does anyone know if you have to reactive Pd/C after performing a CTH or is that only for standard hydrogenations?

akcom

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Re: Catalytic Transfer Hydrogenation: A review
« Reply #11 on: April 25, 2011, 10:20:01 PM »
A more up to date review
Quote
Heterogeneous catalytic transfer hydrogenation and its relation to other methods for reduction of organic compounds
Robert A. W. Johnstone, Anna H. Wilby, Ian D. Entwistle
Chem. Rev., 1985, 85 (2), pp 129–170
DOI: 10.1021/cr00066a003
Publication Date: April 1985

Reduction of  organic compounds is important  syn-
thetically both in the laboratory and in industry.  There
are many methods of  effecting reduction which may or
may not lead to hydrogenation, but in this review only
processes leading t o  the  addition  of  hydrogen  or  re-
placement of  a functional group by hydrogen will  be
considered.  Further, this  review  will  be  concerned
mostly with those  processes t h a t  can  be  effected by
heterogeneous catalysis using molecules  other  than
molecular hydrogen as the  source of  hydrogen. Re-
duction of  organic functional groups can be categorized
into (i) addition of hydrogen to unsaturated groups as,
for example, in the reduction of  ketones to alcohols and
(ii) addition of  hydrogen across single bonds leading to
cleavage  of  functional  groups (hydrogenolysis). Re-
moval of  oxygen as a reductive process, as in the de-
oxygenation  of  oxiranes  to  alkenes,  will  not  be  dis-
cussed.

letters

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Re: Catalytic Transfer Hydrogenation: A review
« Reply #12 on: April 26, 2011, 07:34:04 AM »
catalytic hydrogenation is a good way to hydrogenate alot of functional groups.
it works very well for reducing nitroalkanes to amines, imines to amines, removes benzyl groups and can even remove halogen groups from alkanes sometimes. pd/c is the catalyst of choice for me, 5-10% loading on carbon. ammonium formate is what i use as a hydrogen source. reaction solvent is usually methanol or ethanol.

atara

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Re: Catalytic Transfer Hydrogenation: A review
« Reply #13 on: April 26, 2011, 09:55:36 PM »
Don't forget oximes to amines. Zn/NH4Cl is the cheapest reducing system I've ever heard of.

jon

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Re: Catalytic Transfer Hydrogenation: A review
« Reply #14 on: April 26, 2011, 10:22:06 PM »
i got a paper on that system it uses thf to complex the zinc.
see i've been trying to find the best route to dechlorinate loperamide and ammonium formate pd/c is the winner.
it runs at room temperature it runs in methanol the conversion is 100% and it's chemoselective.
the other reducible group would be that teriary benzylic alcohol on the piperidine ring, i found that yes that system is capable of reducing that moiety but not under those conditions.
it would at 110C or so but not at standard conditions.

but i digress what about homogeneous systems like palladium acetate and ammonium formate?
because the catalyst is in solution it has a higher turnover rate and less is needed.
anyone given that any thought?
« Last Edit: April 26, 2011, 10:24:50 PM by jon »

akcom

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Re: Catalytic Transfer Hydrogenation: A review
« Reply #15 on: April 26, 2011, 11:40:41 PM »
jon, I think it would be cheaper to just use palladium acetate and triphenyl phosphine to side step the solubility issues.  PdOAc2 is so much more expensive :\

jon

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Re: Catalytic Transfer Hydrogenation: A review
« Reply #16 on: April 26, 2011, 11:53:45 PM »
pd acetate is easily made from pdcl2
by treating it with aq sodium hydroxide the pd(oh)II crashes out then, simply react that with acetic acid iirc.

akcom

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Re: Catalytic Transfer Hydrogenation: A review
« Reply #17 on: April 27, 2011, 12:27:13 AM »
I'm not sure its that simple?  Pd(OH)2 is a very stable species. A reference would be much appreciated.  If thats the case then PdOAc2 definitely seems like the way to go

jon

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Re: Catalytic Transfer Hydrogenation: A review
« Reply #18 on: April 27, 2011, 02:15:36 AM »
yeah i think that was wrong i think what you do is precipitate palladium with formalin and naoh wash that and treat it with acetic acid and nitric acid i think that was the correct way.

pyramid

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Re: Catalytic Transfer Hydrogenation: A review
« Reply #19 on: July 01, 2012, 04:46:46 AM »
Unless there is another thread I believe this would be appropriate to post here. I may as well post all the synthesis and not just the last step, the hydrogenation. It is not all OTC but nevertheless maybe someone can find it useful. Well maybe it's just an opportunity to post information and to let you know I have not died from synthetic cannabinoid use...
This is a synthesis of 2C-E hydrochloride starting from 1,4-dimethoxybenzene. The last step is utilizing the CTH reduction and the results are great. I'd like to see more people applying this technique if they can, on all types of varying substrates. Who else will post some practical experience that happened somewhere on the Earth at one point in time?

2-ethyl-1,4-dimethoxybenzene

A 250ml 3-neck RBF containing a stirbar was fitted with a condenser, drying tube, bubbler, thermometer, septa and argon inlet. All glass was flame dried in a stream of argon and a positive pressure of Ar maintained during the initial steps of the procedure.
1,4-dimethoxybenzene (75mmol, 10.362g, stored in vac dessicator for 24h) was added to the flask when cool, followed by dry THF (80ml) freshly distilled from LiAlH4. The flask was cooled in an ice/salt bath to an internal temperature of 0C, and 1.6M n-butyllithium in hexanes (57ml, 1.2eq, 90mmol) was added dropwise during 15minutes.
The pale golden reaction mixture was stirred with cooling for 30 minutes, the Ar cut, then 1-bromoethane (1.5eq, 112.5mmol, 8.34ml) was added over about 5 minutes. After 15 minutes of stirring the ice bath was removed, and during 1 hour the temperature rose to 36C so brief cooling was applied  until 25C. Stirring was then continued overnight at RT.

The next day the solvents were evaporated and the residue taken in H2O/EtOAc (75/50ml), the layers separated, and the aqueous extracted once more with EtOAc (30ml). The organic layer was then washed with H2O (75ml) then brine (50ml), dried on Na2SO4, filtered through a cotton plug and the solvent removed in vacuo and the residue held under vacuum for 30 minutes without stirring on an 80C water bath. A clear, pale yellow oil remained in quantitative yield, MW 166.21. It has a very sweet odor less penetrating than 1,4-dimethoxybenzene but very similar.



4-ethyl-2,5-dimethoxybenzaldehyde

The above substituted benzene (75mmol) was dissolved in AcOH (105ml) followed by the addition of hexamethylenetetramine (2.25eq, 169mmol, 23.66g) and this stirred until complete dissolution. There was then added carefully Trifluoroacetic acid (45ml) which resulted in a slight exotherm and the development of a jade green solution. The reaction mixture was heated to reflux for 6hr, it became orange. The RM was poured into 300ml H2O and left to cool for 30 minutes. The mixture was extracted with EtOAc1 (4x 50ml) and the combined organics washed with sat. NaHCO3 solution until no more CO2 evolution.
This was followed by a wash with H2O (50ml) then brine (50ml) and drying on Na2SO4, filtration, and removal of the solvent in vacuo.
There remained an orange oil, MW 194.22, 12.01g, 61.8mmol, 82.4% yield. Used as such in the next step.

1- Brine/salt had to be added to provoke proper phase separation

4-ethyl-2,5-dimethoxyphenylnitroethene

The above aldehyde (62mmol) was dissolved in iPrOH (25ml) and there was added in sequence nitromethane (1.2eq, 74.4mmol, 3.98ml), AcOH (1ml) and ethylenediamine (10mol%, 370mg). The mixture was swirled and mixed well and allowed to sit at RT for 21h then in the freezer for 3h. Following filtration and washing with iPrOH then recrystallization from minimal iPrOH there was obtained 9.38g of orange needles, 39.5mmol, 63.7% yield. MP: 99-100C

4-ethyl-2,5-dimethoxyphenylnitroethane

The following was based off the general procedure well known by Barium.

A 250ml 3-neck RBF containing a stirbar was fitted with a thermometer on a side neck. There was added EtOAc (50ml) and 96% EtOH (non denatured, 12ml) followed by NaBH4 (4eq, 100mmol, 3.78g). The white suspension was stirred well, a cotton ball was placed loosely in the center neck of the flask, and through the side neck remaining there was added portionwise the nitrostyrene (25mmol, 5.93g) while keeping the temperature at 25-28C, this took 15 minutes with ice cooling, and the solution was stirred at 25C for 30 minutes following addition.
H2O (80ml) was added and the mixture well stirred then transferred to a sep funnel. Drop wise with swirling there was added 50% aq AcOH until no more H2 evolved, then more to dissolve any salts. The layers were separated and the aqueous extracted once more with EtOAc (50ml) and the organic layer washed with H2O (2x 75ml) then brine (50ml). After drying on Na2SO4, filtration and removal of the solvent and holding residue in vacuo on a hot bath for ~30 minutes there was obtained 6.07g of a yellow oil, 25.36mmol, 101% yield, MW 239.27. it was used as such in the next step without purification.

4-ethyl-2,5-dimethoxyphenethylamine hydrochloride

The above nitroalkane was transferred to a 250ml 3 neck flask w/stirbar, Ar inlet and condenser topped with a balloon with MeOH (65ml). H2O (5ml) was added then dry ammonium formate (48h in vac dessicator over CaCl2 flakes, 5.5eq, 137.5mmol, 8.67g) and the mixture stirred for 20 minutes, the NH4COOH had dissolved but there remained some globules of nitroalkane.
There was added in one portion dry 10% Pd/C (450mg, 15% w/w cat:subs ratio EDIT: for clarification, in some patents the catalyst loading is based on 50% wet catalyst, hence the amount here is less if you calculated on 15%... Just to help with any confusion) and the flask warmed with a small flame (such a risk it's awesome) to about 50C which resulted in the MeOH coming to reflux on its own and sustaining for about 30 minutes without external heating. The mixture was stirred for 20h at RT, the balloon never became too filled up.
The RM was then filtered on a pad of celite and washed with 3x 25ml MeOH, 25ml H2O then 25ml MeOH. The filtrate was freed of the bulk of the MeOH by distillation in vacuo and the remaining clear solution put in a sep funnel and dilute HCl was added until acidic. This was washed with PhMe (2x 50ml), the first wash was very slightly yellow and the second colorless. The solution was then basified strongly with NaOH solution which resulted in the formation of an upper pale yellow phase. This was extracted with CH2Cl2 (3x60ml), washed with H2O (50ml), dried on Na2SO4, filtered and the solvent removed completely in vacuo to give 5.24g of an almost colorless oil.

This was taken in iPrOH (50ml) and neutralized with conc HCl, giving a solid mush of product. MTBE (~75ml) was added and the crystals triturated and freed, then this was put in the freezer for 1 hour to complete precipitation. After filtration and washing with MTBE (100ml total) and drying there was obtained 4.512g of snow white needles. FB MW: 209.28    HCl salt: 245.74, 73.4% yield. MP 205-208C, lit value is dubious since different values have been given, who knows how many salt forms there may be. The bioactivity is confirmed.

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Interesting to note the high yield of freebase product, assuming it is mostly pure which is likely. Formation of salts is always lossy anyway. The hydrogenation is just wonderful if you have everything needed, the catalyst can be reused a few times and the yield is high, the products clean. No need for heating to reflux either, except to get the thing going at the beginning(but this is really just warming then it heats itself). It is aqueous and really very easy.. Anyone else out there doing it? Post it! Soon perhaps some other substrates will be added, the more collective information the better... No? It is truly a great method, if you have done any reduction of a nitroalkene/alkane with Zn, Al, LiAlH4... This will be a welcome change! Plus the yields are much much better!
« Last Edit: July 04, 2012, 03:58:28 AM by pyramid »