                      Sodium Borohydride on Wet Clay:
  Solvent-free Reductive Amination of Carbonyl Compounds Using Microwaves

                       Tetrahedron 54, 6293-8 (1998)

                   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.

The reductive amination of carbonyl compounds is one of the most useful
reactions for the synthesis of amines and their derivatives[1] as these
compounds are known to have herbicidal and fungicidal activities,[2] and
constitute important precursors to a variety of agents that are of interest
to pharmaceutical  and agricultural industries.[3] The Borch reduction
using sodium cyanoborohydride [NaBH3CN] [4] reductive animation using
sodium triacetoxyborohydride [NaBH(OAc)3] [5] 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.[6] 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.[7] Microwave (MW) heating
has been used for the rapid synthesis of a variety of organic
compounds[8-11] both in solution phase as well as under solvent-free
conditions.[10,11] 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[10,11]
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,[11] we have discovered methods for the rapid
synthesis of imines and enamines via reactions that are catalyzed by
clay[11i] and Envirocat reagent, EPZG,[11j]  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.

RESULTS AND DISCUSSION

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.[12] 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-chlorobenzylamine (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,[11i] 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.[13,14]  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.[5,6]

R1R2C(OH)-NR4R5  --> R1R2C=N+R4R5  -->  R1R2CH-NR4R5    [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).

[Scheme]

R1R2CO + H2N-R3  -->  R1R2C=NR3  -->  R1R2CH-NHR3

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.

{Editing notes on table: Ariel font 10. Tab stops at: 0.4", 2.3", 3.6", 4.1", 4.6", 5.5"}

Table. Reductive Amination of Carbonyl Compounds using NaBH4 Supported on K 10 Clay
------------------------------------------------------------------------------------------------------------------------------------------
Entry   Carbonyl Compounds      Amines  Time    Yield   m.p.(C) or b.p. (C)/torr
                        (min)   %       Observed        Reported
------------------------------------------------------------------------------------------------------------------------------------------
1       Benzaldehyde    Aniline <5.00   97      37-38   35.5-37.8 [17]
2       Benzaldehyde    n-Heptylamine   <5.00   94      167-169 [c]     166-170 [18]
3       Benzaldehyde    Tyramine        1.50    90      141-142 143 [19]
4       Salicylaldehyde Aniline <5.00   96      111-112 113 [20]
5       Salicylaldehyde p-Nitroaniline  1.00    88      136-137 138 [21]
6       p-Chlorobenzaldehyde    Aniline 0.50    90      209-211 [c]     210-211 [16]
7       p-Chlorobenzaldehyde    o-Aminophenol   0.75    84      108-109 109 [21]
8       p-Anisaldehyde  Aniline 0.25    93      46-48   48-49 [16]
9       p-Anisaldehyde  p-Aminophenol   0.75    81      101-103 102-103 [23]
10      p-Nitrobenzaldehyde     Aniline 1.25    78      67-69   67-68 [22]
11      3,4-Dimethoxybenzaldehyde       p-Chloroaniline 0.50    91      122-123 123 [21]
12      Isobutyraldehyde        Aniline 1.00    78      204-206 [c]     206 [24]
13      2-Ethylbutyraldehyde    Aniline 0.75    87      113-115 [e]     114-115 [25]
14      2-Ethylbutyraldehyde    n-Decylamine    1.50    86      66-69/8 f
15      2-pyrrolyl-carbaldehyde homoveratrylamine       1.50    81      145-147 147 [21]
16      Acetophenone    Aniline 1.50    92      121-124/3       122-124/3 [28]
17      Acetophenone    Benzylamine     2.00    66      178-180[c]      179-181 [5]
18      Cyclohexanone   Aniline 1.00    89      105-108/3       112-113/3 [26]
19      4-Methylcyclohexanone   Benzylamine     2.00    85      98-99[e]        97-98 [27]
20      Cycloheptanone  Propylamine     0.75    79      205-207[c]      207-208 [5]
21      4746-97-8 [g]   Benzylamine     1.50    91      241-243[d]      245-246 [5]
22      3-Pentanone     Aniline 1.00    83      83-86/8 56-67/3-4 [26]
23      2-Heptanone     Morpholine      2.00    81      150-151[c]      151-153 [5]
24      2-Heptanone     Piperidine      2.00    78      159-161[c]      160-161 [5]
------------------------------------------------------------------------------------------------------------------------------------------
[a]  Time for the reduction of in situ generated Schiff's bases in microwave oven. The time is in minutes. The time, <5.00 min. refers to the reductions at room temperature that are completed on simple mixing of the Schiff's base with NaBH4-wet clay.
[b]  Unoptimized yields of purified bases that exhibited physical and spectral properties in accord with the assigned structures.
[c]  Hydrochloride salt.
[d]  Oxalate salt.
[e]  p-Toluenesulfonyl derivative.
[f]  See experimental section.
[g]  CAS registry #: 1,4-cyclohexanedione mono-ethylene ketal

EXPERIMENTAL SECTION

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 Perkin-Elmer
1310 spectrophotometer. NMR spectra were recorded in CDCl3 on a Jeol
Eclipse (300 MHz for (1)H NMR and 75 MHz for (13)C 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 montmorillonite 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 K10 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 sec (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. [details omitted of analytical data for this
cmpd. {Analytical details are omitted at this point}

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 (1.53 g) to which water (1 mL) was added and the reaction
mixture was irradiated in MW oven for 45 sec at its full power. Upon
completion of the reaction, as monitored on TLC, the product was extracted
into methylene chloride (3x 15 mL). The removal of the solvent under
reduced pressure gave the free base in 79 % yield. HCl 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-anisaldehyde with aniline
(entry 8), at a relatively larger scale (50 mmol), undergoes completion in
30 sec to afford N-phenyl-p-methoxybenzylamine in 91% yield.

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Presented, in part, at the 215th American Chemical Society National Meeting
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