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Author  Topic:   NaBH4 / wet clay (paper) 
Member   posted 06-17-98 09:09 AM          

Sodium Borohydride on Wet Clay: Solvent-free Reductive Amination

Carbonyl Compounds Using Microwaves

Rajender S. Varma and Rajender Dahiya

Abstract: A solvent-free reductive amination of carbonyl compounds
by wet montmorillonite K 10 clay supported sodium borohydride is described;
microwave irradiation facilitates the Procedure- 0 1998 Elsevier Science
Ltd. All rights reserved.

The reductive amination of carbonyl compounds is one of the most useful
reactions for the synthesis of amines and their derivatives as these compounds
are known to have herbicidal and fungicidal activities, and constitute
important precursors to a variety of agents that are of interest to pharmaceutical
and agricultural industries. The Borch reduction using sodium cyanoborohydride
[NaBH3CN] and reductive animation using sodium triacetoxyborohydride [NaBH(OAC)3]
are the two very popular methods to achieve this transformation. However,
the first method has the risk of residual cyanide in the products or in
the workup waste stream whereas the later involves the use of corrosive
acetic acid. Recently, the N-alkylation of primary aromatic amines has
also been reported using NaBH4 that is conducted in sulfuric acid medium.
Consequently, there is a need for the development of a manipulatively easy
and an environmentally friendly method for the reduction of in situ
generated Schiff's bases.

Heterogeneous reactions facilitated by supported reagents on various
solid inorganic surfaces have received attention in recent years because
of the greater selectivity and simple reaction work-up. Microwave (MW)
heating has been used for the rapid synthesis of a variety of organic compounds
both in solution phase as well asunder solvent- free conditions. 
The salient features of the microwave approach coupled with the use of
mineral supported reagents or catalysts are the enhanced reaction rates.
formation of pure products in high yields and the ease of manipulation.
Further, the solventless microwave-assisted reactions  are now gaining
popularity as they provide an opportunity to work with open vessels, thus
avoiding the risk of high pressure development and with a possibility of
upscaling the reactions on preparative scale.

During the course of our ongoing program to develop environmentally
benign solvent-free methods, we have discovered methods for the rapid synthesis
of imines and enamines via reactions that are catalyzed by clay and Envirocat
reagent, EPZG,  wherein elimination of water is facilitated by exposure
to microwaves. Herein, we report a facile method for the synthesis of secondary
and tertiary amines using a solvent-free system, NaBH4-wet clay coupled
with microwave activation.



We investigated the reducing ability of NaBH4-wet clay for the reduction
of in situ generated Schiff's bases. The solid state reductive amination
of carbonyl compounds is explored on various inorganic solid supports such
as alumina, clay, silica etc. and found that among these materials clay
afforded the best results. Clay not only behaves as an acid but also provides
water from its interlayers that is responsible for the acceleration of
the reducing ability of NaBH4. The important role of clay is apparent from
the fact that only poor yield (~10%) was obtained without this support
as exemplified for the product, N-phenyl-p-chlorobenzylarnine (Table,
entry 6), Although these reactions are very facile yet the efficiency may
be further enhanced by conducting the reactions in partially sealed containers.

The process in its entirety involves a simple mixing of in situ
generated imines, with 10% NaBH4-wet clay and irradiating the reaction
mixture in an unmodified household microwave oven for the time specified
in the Table. The reagent is more effective when the Schiff s base is first
mixed with NaBH4 and clay and then wetted with water. A simple extraction
of the product from the solid support affords the corresponding amines
in high yields. In some cases, the reduction of imines is completed immediately
upon mixing with clay supported NaBH4 at room temperature. However, the
reactions involving Schiff s bases generated from cyclohexanone and aniline
(entry 12) and aliphatic aldehydes and amines (entry 14) require a relatively
longer time for completion. The reduction of the substrates bearing electron
withdrawing substituents (entries 5, 10) is relatively slow in comparison
to those with electron donating groups (entries 8, 9). No side product
formation is observed in any of the reactions investigated. Interestingly,
the dehalogenation of the compounds (entries 6, 7 and 11) is not observed
under these conditions.  For low boiling reactants, the reaction mixtures
are irradiated with intermittent heating [pulsed sequence with an interval
of 1 min between two successive irradiations of 2 min each at low MW power
(20%)]. This pulse protocol is required to maintain the bath temperature
at ~65 C to avoid the loss of low boiling n-propylamine (entry 20, see
details in experimental section).

In the reactions of ketones with secondary amines (entries 23, 24),
where enamine formation is expected, the intermediate carbinol amines dehydrates
to generate iminium ions in the presence of acidic K 10 clay which, in
turn, accept hydride ions from NaBH4 to afford tertiary amines (Eqn. 1).
This acidity dependent generation of hydride species from NaBH4 on clay
surface, which is responsible for the reduction of the Schiff bases, has
not been fully exploited.

[Eqn 1]

That the effect may not be purely thermal is evident from the
fact that for similar product yields a much longer time period is required
for completion of the reaction (5h, entry 6) at the same temperature of
65 'C using an alternate heating mode (oil bath).

In conclusion, we have developed a facile and practical method for the
reductive amination of carbonyl compounds under solvent-free conditions
using NaBH4-wet clay, that is accelerated by microwave irradiation.




General. All reagents were purchased from Aldrich Chemical Co.
or Lancaster Synthesis Inc. and were used as received. Some aldehydes were
distilled prior to use. A Sears Kenmore microwave oven (900 Watts) equipped
with a turntable was used for microwave heating. An alumina bath (neutral
alumina: 125 g, mesh ~150, Aldrich; bath: 5.7 cm diameter) was used as
a heat sink inside the MW oven to irradiate the reaction mixtures in all
experiments. TLC was performed on silica gel plates obtained from Analtech,
Inc. using Hexane:EtOAc (9:1, v/v) as the solvent system. Melting points
were determined on a Mel-Temp II hot stage apparatus using Fluke 51 K/J
digital thermometer and are uncorrected. IR spectra were recorded on a
PerkinElmer 13 10 spectrophotometer. NMR spectra were recorded in CDC13
on a Jeol Eclipse (300 MHz for H NMR and 75 MHz for 13C NMR) spectrometers
using TMS as an internal standard. Mass spectra-were recorded on a Hewlett
Packard 5890 mass spectrometer (70 eV) using a GC/MS coupling or direct
inlet system. The identity of the compounds were confirmed by comparison
of their physical and spectral data with those reported in the literature
including their derivatization into various salt forms. The reagent, 10%
NaBH4-clay, is prepared by mixing NaBH4 (0.5 g) with montmoritionite K
10 clay (4.5 g) in solid state using a pestle and mortar.

CAUTION. Although we did not encounter any accident during these
studies, we recommend extreme caution for reactions conducted on larger
scales because of the possible higher localized temperatures attained in
the microwave oven.

Typical Procedure. The synthesis of N-phenyl-p-chlorobenzylamine
is representative of the general procedure employed. A mixture of p-chlorobenzaldehyde
(0.7 g, 5 mmol), aniline (0.455 g, 5 mmol) and montmorillonite KI0 clay
(0.1 g) contained in a 25 mL beaker was placed in an alumina bath inside
the microwave oven and irradiated for 2 min. The in situ generated Schiff
s base was mixed thoroughly with freshly prepared NaBH4-clay (5.0 mmol
of NaBH4 on 1.72 g of reagent) and water (1 mL). The reaction mixture was
again irradiated for 30 see (65 'C). Upon completion of the reaction, monitored
on TLC, the product was extracted into methylene chloride (3x 15 mL). The
removal of solvent under reduced pressure provided pure N-phenyl-p-chlorobenzylamine
in 90% yield. The identity of the product was confirmed by formation of
the hydrochloride salt, m.p. 209-211 'C (EtOAc-MeOH) (lit. m.p. 210-211
'C). 16

N-(2-Ethylbutyl)-1-decylamine (entry 14). The same procedure described
for the preparation of N-phenyl-p-chlorobenzylamine provided a free
base in 86 % yield, b.p. 66-69 'C/8 torr.

N-(Propyl)aminocycloheptane (entry 20): A mixture of cycloheptanone
(0.56 g, 5 mmol), n-propylamine (0.46 g, 7.5 mmol) and K 10 clay (0. 1
g) contained in a small beaker was placed in an alumina bath (heat sink)
and irradiated for 6 min in a MW oven at its 20% power using pulsed method
(one min cooling between two successive irradiations of 2 min each). The
in situ generated Schiff s base was mixed with sodium borohydride (0. 19
g, 5 mmol) and K 10 clay (1.5 3 g) to which water (I mL) was added and
the reaction mixture was irradiated in MW oven for 45 see at its full power.
Upon completion of the reaction, as monitored on TLC, the product was extracted
into methylene chloride (3xl5 mL). The removal of the solvent under reduced
pressure gave the free base in 79 % yield. HCI salt (EtOAc-MeOH), m.p.
205-207 'C (lit. m.p. 207-208 C).5

All the results reported in the Table refer to the reactions that are
conducted on a 5 mmol scale. The reaction of p-anisaidehyde with
aniline (entry 8), at a relatively larger scale (50 mmol), undergoes completion
in 30 see to afford N-phenyl-p-methoxybenzylamine in 91% yield.


Member   posted 06-17-98 09:13 AM          
So would this be a good way to get n-formyl-mda or what??
Member   posted 06-17-98 07:05 PM          
Quirks-Great job on getting the ref! Any chance you could post the missing table as well as the lit. refs of the article? (Sorry to be so demanding, but I thirst for info!)
BTW: I'll be happy to return the favor re: any refs/docs you have trouble getting a hold of.


Member   posted 06-17-98 07:09 PM          
Quirks- As to N-formyl-MDA, what would your reagents be, hypothetically? MD-P2P + Formamide? Are you contemplating some sort of MW assisted Leukart reaction?
I don't think that the N-formyl complex will form simply form MW radiation alone since Leukart rxns require pressure as well. Could be wrong though.


Member   posted 06-17-98 07:22 PM          
Now that we have the paper on the Hive, I propose two areas of required further investigation regarding the hypothetical production of Honey from MD-P2P & MeNH2:
1. Containment of MeNH2: Well since MeNH2 is a gas @RT, it must somehow be prevented from evap. and escaping (and posing an explosion risk!)

2. Removal of H2 gas: Since in all likelyhood H2 gas will evolve from this rxn. a means for safely removing should be planned.

Now as to #2, there is always venting, i,e drawing out the H2 gas via a small tube w/ suction. Though I think a better idea would be some substance that would absorb the H2 gas in the chamber as well as venting. Any thoughts?

As for #1, perhaps an easier way would be to form /isolate the immine before MW, this way conventional solvent systems might be used for this stage. Otherwise, some sort of sealed Teflon rxn vessel may be required.

Or... ?


Member   posted 06-17-98 07:46 PM          
Yes Yes Yes
Member   posted 06-18-98 10:48 AM          
There was a thread in imimes a while back but I can't find it now @#$! We need a search engine...
Scooby Doo
Member   posted 02-18-99 07:47 AM          
These are some observations when dreaming with the reductive amination using microwaves. If any Bee has thoughts on how to improve this method I would greatly appreciate any ideas.
NH3 was bubbled through 100 ml of DMF until saturation (1.15 grams of NH3 in DMF at 40deg, the DMF became quite hot). The ref called for a 1:1 mole ratio, however due to the natoure of the amine we are interested in I believed a lot more would be needed. The reactions were carried out on a 50 mmol scale.

8.9 g of not MDP2P
At least .85 g of NH3
1g of K10 clay

1st run
All reagents added and the beaker was placed in a alumina bath (approx 500g). The reaction mixture was irradiated at 20% power or 150 watts for 2 minutes. Nothing seemed to have taken place. Apart form a slight increase in temp 5 deg to 45 deg. Next the NaBH4-clay was added to the reaction which resulted in a vigorous reaction, Then 10 g of water was added and the reaction placed back into the microwave and nuked for a further 30 seconds. Cleanup consisted of adding 500 mls of water and filtering. Then extracting with DCM. The smell was definitely right however the product produced was to small to be crystallised out.

2nd Run

All was the same as above except 10 g of clay was added and the microwave power was 40% or 350 watts. There seemed to be a definite reaction after the first 2 minutes were a lot of bubbling was evident with the reaction temp up near 90 deg. Iím not sure if this was the reaction or un-reacted NH3 being liberated. Once again when the NaBH4-clay and water was added and nuked for 30 sec a vigorous reaction was noted. The mixture was extracted with ether,dryed and HCl bubbled through the reaction. Again smell was on the money but the amount was still too small for a good crystallisation. Definitely more than the 1st run but still not enough.

From getting a feel for this reaction I believe that more power is need plus plenty more NH3.


unregistered   posted 02-20-99 11:17 AM           
This reaction is really two reactions. The first reaction is the formation of the imine. Microwave heating is not required or desirable. If you have Morrison and Boyd, Organic Chemistry see 18.13.
I think the formation of the imine must not require much energy because there is no mention of it in any synthesis text. It must be nearly spontaneous.
The great advantage in this microwave reduction of the imine is the use of common NaBH3.
Member   posted 02-20-99 01:42 PM          
If scooby doo can smell freebase when animating with ammonia then this likely has good promise with methylamine eh?
unregistered   posted 02-20-99 05:01 PM           
Here is a procedure to make imine from an organic lab book. Look under semicarbazone derivatives of aldehydes and ketones.
Heat for 2 hours under reflux on the steam bath a mixture of 0.5 gram of carbonyl compound , 0.5 gram hydroxylamine hydrochloride (or other amine), 3 ml pyridine, and 3 ml of absolute ethanol. Remove the solvent by evaporation.

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