Cherrie Baby:

CTH - Catalytic Transfer Hydrogenation

This looks like a very promising road to explore for reseach. The chemicals
involved are just 5% or 10% Pd/C and ammonium formate. How would polymer
supported Pd work? The reaction conditions are mild [reflux at 100 C.] The
ammonium formate acts as a hydrogen donor (sodium formate works too). This
interests me cos' my hardware shop sells ammonium formate solution as
kettle descaler. It could interest other bees in the UK.

Eg. Ketones were reduced to alkanes [sounds a lot better than
Wolff-Kischner or Clemmensen for this.]

Alkens are reduced to alkanes.

See J. Chem. Education 74(4), p430 (1997) or Tetr. Lett. 1988, 29, 3741.

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Cherrie Baby:

Azides and nitroalkanes to amines and of carbonyl groups to alkanes.

CTH is an easy reduction method to use. It required easy to obtain reagents
and mild reaction conditions. The only problem is obtaining the catalyst -
but remember that the catalyst can be reused - almost forever - so that the
initial investment pays dividends in the long term.

General procedure for the reduction of Azides to Amines [from Ref 2.]

A mixture of 1 mole of azide, 4 moles of anhydrous ammonium formate and 5%
Pd-C (6-15% of the azide by weight) in 100 mL of methanol is stirred for
3-4 hours at ambient temperature. The catalyst is removed by filtration and
the product is isolated by standard procedures. Yield 74-93%.

General procedure for the reduction of nitro-alkanes. [from Ref 1.]

To a stirred suspension of an appropriate nitro compound (5 mmol) and 10%
Pd-C (0.2 - 0.3 g) [see Note 1] in dry methanol (10 mL), anhydrous ammonium
formate was added (23 mmol) in a single portion. The resulting reaction
mixture (slightly exothermic and effervescent) was stirred at room
temperature for 3-40 min under argon[see Note 2], the catalyst was removed
by filtration through a celite pad and washed with dry methanol (10 mL).
The filtrate was evaporated either under reduced or at normal pressure. The
resulting residue was triturated with water (10 mL - 25 mL), product was
extracted with an organic solvent (i.e. ether, DCM or chloroform) and dried
over Na2SO4. The organic layer on evaporation gave the desired amino
derivative. Some products were directly converted into the HCl-salt with
ethereal-HCl without evaporation of ether layer.

In most cases the reaction is over within 15-30 min with nitro-alkanes.
These results demonstrate a rapid versatile and selective reducing system
for wide variety of nitro-compounds in the presence of other functional
groups for e.g. -CN. > C=O, etc. Ammonium formate also has the advantages
of being readily available, inexpensive, stable and nontoxic and can be
used in conjunction with either Pd-C or Raney-Nickel catalysts. Moreover,
it may be added to the reaction in a single portion and products can be
easily separated from the reaction mixture. This procedure will therefore
be of general use for the preparation of amines specifically in cases where
rapid mild reduction is required.

A typical procedure for reduction of aldehydes and ketones. [ref. 4]

To a stirred suspension of an appropriate aldehyde or ketone (7.5 mmole)
and 10% Pd-C (0.350 g) in glacial acetic acid (10 ml), the anhydrous
ammonium formate (38 mmole) was added in a single portion under argon. The
resulting reaction mixture was stirred at 110°C +/- 5°C for 10-30 min. The
progress of reaction was monitored by TLC and GC. After completion of the
reaction, 50 ml of CHCl3 was added, and the catalyst was removed by
filtration through a celite pad and washed with CHCl3 (20 ml). The combined
organic filtrate was washed with water (20 ml x 2), then with saturated
sodium bicarbonate solution (20 ml x 2), and dried over anhydrous Na2SO4.
The organic filtrate on evaporation, either under reduced pressure or at
normal pressure, afforded the desired product, which was further purified
by column chromatography over silica gel using an ethyl acetate:hexane
mixture as the mobile phase. The phenolic derivatives were obtained by
direct evaporation of filtrate after removal of the catalyst.

Yields from a variety of methoxy ring-substituted benzaldehydes to the
corresponding methoxy-ring substituted toluene varied from 57-70% but
benzaldehyde required a longer reduction time and gave only 10% yield of
toluene.

The reduction of acetophenone was sluggish. After a 30 min reaction time
interval, the product/substrate ratio in the reaction mixture was 1/5
observed by GC analysis (as described above, except initial temperature
hold time 3 min). However, upon adding an additional amount of HCO2NH4 and
increasing the reaction time up to 4 hr. the product/substrate ratio
changed to 55/44.

In the case of benzaldehyde, 1.5% toluene, 34% benzyl alcohol (retention
time 4.9 min) and 60% high boiling by-product (retention time 8.9 min) were
observed in the reaction mixture after 20 min at 85°C. Prolonging the
reaction time slowly increases the concentration of toluene (Table 1) with
reduction of benzyl alcohol. This important observation provides evidence
that reduction of aldehydes and ketones to hydrocarbons proceeds via the
alcohol intermediate, which is further confirmed by our finding that
diphenylmethanol is rapidly converted to diphenylmethane under the
experimental conditions reported here. The poor yield of toluene may be due
to its low boiling point.

These results demonstrate a rapid, mild and selective reduction of a wide
variety of aromatic aldehydes and ketones to methylene derivatives under
moderate reaction conditions and can be an attractive alternative for
Wolff-Kishner or Clemmensen reduction, provided other functionalities such
as nitro or halo substituents are not present in the substrate, since these
groups are readily reduced or displaced. We have found, however, this
procedure is not applicable for reduction of conjugated olefinic carbonyl
groups, as the C-C double bond is preferentially reduced.

Other Applications of CTH with Amm. Formate are: dehalogenation of aromatic
chlorocarbons, deprotection of peptides and reduction of hydrazones and
azides to hydrazines.

Note 1 - Other catalysts can be used. Polymer supported Pd catalyst should
         work. Raney Ni often works and Urushibara Ni should work as well
         [but these are untested].

Note 2 - Argon atmosphere is not required. This is only used by research
         scientists to create reproducible reaction conditions.

Note 3 - yields varied between 31% to 98%. Lower yields were obtained with
         low boiling point compounds such as n-propylamine (31%) and
         n-butylamine (49).


References:
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1. S Ram & R E Ehrenkaufer. A General Procedure for Mild Rapid Reduction of
   Aliphatic and Aromatic Nitro Compounds Using Ammonium Formate as a
   Catalytic Hydrogen Transfer Agent. Tetrahedron Letters 25(32), 3415-3418
   (1984).

2. S Ram & R E Ehrenkaufer. Ammonium Formate in Organic Synthesis: A
   Versatile Agent in Catalytic Hydrogen Transfer Reductions. Synthesis,
   1988, 91-95.

3. A Barrett & C Spilling. Transfer Hydrogenation: A Stereospecific method
   for the Conversion of Nitro Alkanes to Amines. Tetrahedron Letters
   29(45), 5733-4 (1988).

4. S Ram & L Spicer. Reduction of Aldehydes and Ketones to Methylene
   Derivatives using Ammonium Formate as a Catalytic Hydrogen Transfer
   Agent. Tetrahedron Letters 29(31), 3741-4 (1988).

