Phase transfer catalyzed process for borohydride reductions of carbonyl compounds

A process for the reduction of carbonyl compounds by an alkali or alkaline-earth metal borohydride in the presence of a phase transfer catalyst which is an N-benzyl-N,N-bis (2-hydroxyethyl)cocoammonium halide.

This invention pertains to phase transfer catalyzed reduction of carbonyl 
compounds by an alkali or alkaline-earth borohydride. In particular, it 
relates to the use of an N-benzyl-N,N-bis(2-hydroxyethyl)cocoammonium 
halide as the phase transfer catalyst. 
BACKGROUND OF THE INVENTION 
Phase transfer catalysis ("PTC") is a synthesis method which allows the use 
of relatively simple two-phase reaction systems in the place of solvent 
systems which may be toxic and/or expensive. 
In fundamental terms, PTC employs a phase transfer catalyst which 
facilitates the transfer of a reactive species from the first phase, 
normally aqueous, into the second phase, normally organic, where the 
desired reaction can take place. For example, a phase transfer catalyst 
may be used to transport a cyanide ion from an aqueous solution of sodium 
cyanide to an organic solution of an alkyl halide where the cyanide ion 
reacts with the alkyl halide to form alkyl nitrile. 
PTC is known to be a valuable technique for accomplishing a wide range of 
reactions. For example, PTC is known to facilitate nucleophilic 
substitution reactions, hydroxide transfer, esterification, oxidation and 
reduction. Specifically, U.S. Pat. No. 3,992,432 claims the use of certain 
quaternary salts as phase transfer catalysts to effectuate reactions such 
as displacement reactions (for example the earlier described preparation 
of alkyl nitrile), oxidation of organic compounds with inorganic oxidizing 
agents, ester saponification and the conversion of carbonyl compounds to 
alcohols. The quaternary salts for use as phase transfer catalysts taught 
and claimed in U.S. Pat. No. 3,992,432 are of the general formula (R.sub.1 
R.sub.2 R.sub.3 R.sub.4 M).sup.+ X.sup.- wherein M is nitrogen, arsenic, 
phosphorus, antimony or bismuth; X is a halide or hydroxy ion; and 
R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are monovalent hydrocarbon radicals 
having a total sum of 18 to 70 carbon atoms, one of which may be further 
substituted by a quaternary group so the salt is represented by R.sub.1 
[(R.sub.2 R.sub.3 R.sub.4 M).sup.+ X.sup.- ].sub.2. In Example 41 of U.S. 
Pat. No. 3,992,432, 2-octanone is reduced to 2-octanol by sodium 
borohydride in the presence of the phase transfer catalyst 
tricaprylylmethyl ammonium chloride. 
Reduction of the aromatic compound C.sub.6 H.sub.5 (C:OX) (where X is halo 
and the benzene ring may be optionally substituted) to C.sub.6 H.sub.5 
(CH.sub.2 OH) with an alkali or alkaline-earth metal borohydride in the 
presence of a phase transfer catalyst (which may be a quaternary ammonium 
compound) is known from GB 2 155 464 A. 
Also, the article "N-Dodecyl-N-methylephedrinium Bromide: a Specific 
Catalyst for the Borohydride Reduction of Carbonyl Compounds under 
Phase-Transfer Conditions" (Stefano Colonna and Roberto Fornasier, 
Synthesis, August 1975, pages 531-2) compares the performance of five 
phase transfer catalysts in the reduction of 2-octanone to 2-octanol with 
sodium borohydride. Among the five phase transfer catalysts reported by 
Colonna et al. are N-dodecyl-N-methylephedrinium bromide and 
bis[2-hydroxyethyl]-dodecylmethylammonium bromide (referred to in Colonna 
et al. as "bis[2-hydroxyethyl]-dodecylmethylaminium bromide"). Colonna et 
al. also suggest on page 532 the presence of a hydroxy group in the 
catalyst enhances the rate of reduction. In a separate article, (Journal 
of the Chemical Society Perkin Trans I, "Asymmetric Induction in the 
Borohydride Reduction of Carbonyl Compounds by Means of Chiral 
Phase-transfer Catalysts. Part 2.", 1978, pages 371-3). Colonna and 
Fornasier report that to achieve asymmetric induction in the borohydride 
reduction of carbonyl compounds under phase-transfer conditions, the 
hydroxy-group must be in the .beta. position to the `onium` function and 
the catalyst must be conformationally rigid. 
The above-mentioned references do not disclose that 
N-benzyl-N,N-bis(2-hydroxyethyl)cocoammonium halides are superior 
phase-transfer catalysts in processes for reducing carbonyl compounds by 
an alkali or an alkaline-earth metal. 
Surprisingly, it has been found that in the alkali or alkaline-metal earth 
borohydride reduction of carbonyl compounds use of an 
N-benzyl-N,N-bis(2-hydroxyethyl)cocoammonium halide as a phase transfer 
catalyst provides a more rapid reduction reaction when compared with known 
phase transfer catalysts. The process of the current invention is 
particularly useful in the reduction of ketones to the corresponding 
alcohols, such as the reduction of 2-octanone to 2-octanol. 
SUMMARY OF THE INVENTION 
Accordingly, the current invention is a process for conducting a reduction 
reaction in a two-phase reaction system, the process comprised of reducing 
carbonyl compounds by an alkali or an alkaline-earth metal borohydride in 
the presence of a phase transfer catalyst which is an 
N-benzyl-N,N-bis(2-hydroxyethyl)cocoammonium halide.

DETAILED DESCRIPTION OF THE INVENTION 
The current invention is a process for conducting a phase transfer 
catalyzed reduction reaction in a two-phase reaction system. The process 
is comprised of reducing a carbonyl compound by an alkali or 
alkaline-earth metal borohydride in the presence of an 
N-benzyl-N,N-bis(2-hydroxyethyl)cocoammonium halide as a phase transfer 
catalyst. 
In the current phase transfer catalyzed synthesis process, an alkali or 
alkaline-earth metal borohydride is present in an aqueous first phase and 
a carbonyl compound is present in the organic second phase. To reduce the 
carbonyl compound, the borohydride must be transported from the aqueous 
first phase to the organic second phase by a phase transfer catalyst. It 
has been found that use of an N-benzyl-N,N-bis(2-hydroxyethyl)cocoammonium 
halide as the phase transfer catalyst greatly facilitates reduction of 
carbonyl compounds. 
Non-limiting example carbonyl compounds which may be reduced by the phase 
transfer process of the current invention include aliphatic ketones, such 
as methylethyl ketone, octanone and cyclohexanone; aryl ketones, such as 
benzophenone and substituted benzophenones; alkylaryl ketones, such as 
acetophenone and propiophenone; aliphatic aledehydes, such as 
butyraldehyde and octaldehyde; and aryl aldehydes, such as benzaldehyde 
and tolualdehyde. Mixtures of carbonyl compounds may also be reduced by 
the process of the current invention. 
Any compound which will contribute a borohydride ion for reduction of the 
carbonyl compound may be used in the current process. Of particular 
utility are alkali and alkaline-earth metal borohydrides, such as sodium 
borohydride and potassium borohydride. 
As demonstrated by the following non-limiting examples, 
N-benzyl-N,N-bis(2-hydroxyethyl)cocoammonium halides are surprisingly 
superior phase transfer catalysts when compared to known phase transfer 
catalysts in the reduction of carbonyl compounds. In particular, 
N-benzyl-N,N-bis(2-hydroxyethyl)cocoammonium chloride is a superior phase 
transfer catalyst for such reduction reactions. 
EXAMPLE 1 
Equimolar comparison of N-benzyl-N,N-bis(2-hydroxyethyl)cocoammonium 
chloride and (-)-N-dodecyl-N-methylephedrinium bromide as phase transfer 
catalysts in reduction of 2-octanone to 2-octanol 
Two 250 ml flasks fitted with mechanical stirrer, condenser and thermometer 
were each charged with 2-octanone (6.44 g, 0.05 mol) and toluene (30 ml). 
As catalyst, N-benzyl-N,N-bis(2-hydroxyethyl)cocoammonium chloride (0.0005 
mol), available from Akzo Chemicals Inc. under the product name Armak 1733 
(75% active component solution), was added to the first flask and 
(-)-N-dodecyl-N-methylephedrinium bromide (0.0005 mol) available from 
Aldrich Chemical Co., was added to the second flask. Hexadecane (1.0 g) 
was added to each flask as an internal GLC standard. Potassium borohydride 
(1.63 g, 0.03 mol) was added to each reaction mixture along with 50 ml of 
water. At this point, stirring and timing were started. The stirrer speed 
setting was 600 rpm. Periodically, each stirrer was stopped and a sample 
of each organic phase taken for GLC analysis. These results are reported 
in FIG. 1. 
The data reported in FIG. 1 amply demonstrate that, on a mole for mole 
basis, the new phase transfer catalyst 
N-benzyl-N,N-bis(2-hydroxyethyl)cocoammonium chloride surprisingly 
provides a more rapid reduction of 2-octanone to 2-octanol when compared 
to the phase transfer catalyst (-)-N-dodecyl-N-methylephedrinium bromide 
known from Colonna et al., Synthesis, August 1975 as discussed above. 
EXAMPLE 2 
Weight basis comparison of N-benzyl-N,N-bis(2-hydroxyethyl)cocoammonium 
chloride and (-)-N-dodecyl-dimethylephedrinium bromide as phase transfer 
catalysts in reduction of 2-octanone to 2-octanol. 
The rate of reduction of 2-octanone to 2-octanol catalyzed by the new phase 
transfer catalyst N-benzyl-N,N-bis(2-hydroxyethyl)cocoammonium chloride 
was compared to the same reduction reaction catalyzed by the phase 
transfer catalyst (-)-N-dodecyl-N-methylephedrinium bromide known from 
Colonna et al., Synthesis, August 1975. A procedure substantially similar 
to that of Example 1 was employed except 0.16 g of each catalyst in their 
commercially available forms and concentrations were used in each 
reduction reaction. The results are reported in FIG. 2. 
Placing the two catalysts on an equal weight basis puts the new catalyst 
N-benzyl-N,N-bis(2-hydroxyethyl)cocoammonium chloride at a disadvantage 
since its commercially available form is only 75% active. In spite of this 
disadvantage, the new N-benzyl-N,N-bis(2-hydroxyethyl)cocoammonium 
chloride surprisingly out performed the known 
(-)-N-dodecyl-N-methylephedrinium bromide. 
EXAMPLE 3 
Weight basis comparison of N-benzyl-N,N-bis(2-hydroxyethyl)cocoammonium 
chloride and N-methyl-N,N-bis(2-hydroxyethyl)cocoammonium chloride as 
phase transfer catalysts in reduction of 2-octanone to 2-octanol 
The rate of reduction of 2-octanone to 2-octanol catalyzed by the phase 
transfer catalyst of the current invention 
N-benzyl-N,N-bis(2-hydroxyethyl)cocoammonium chloride was compared to the 
same reduction reaction catalyzed by the known phase transfer catalyst 
N-methyl-N,N-bis(2-hydroxyethyl)cocoammonium chloride, available from Akzo 
Chemicals Inc. under the product name Ethoquad C12. Procedures 
substantially similar to those of Example 1 were employed except the two 
catalysts were compared on a 10 wt. % basis and a 5 wt. % basis. Also, a 
reduction reaction was carried out using 2.5 wt. % 
N-benzyl-N,N-bis(2-hydroxyethyl)cocoammonium chloride with no 
corresponding reduction reaction using 2.5 wt. % 
N-methyl-N,N-bis(2-hydroxyethyl)cocoammonium chloride. The results are 
reported in FIG. 3 and FIG. 4. The phase transfer catalyst of the current 
invention out-performed N-methyl-N,N-bis(2-hydroxyethyl)cocoammonium 
chloride even though N-benzyl-n,N-bis(2-hydroxyethyl)cocoammonium chloride 
is disadvantaged in a weight for weight comparison because it is of 
greater molecular weight. 
EXAMPLE 4 
Comparison of N-benzyl-N,N-bis(2-hydroxyethyl)cocoammonium chloride and 
(-)-N-dodecyl-N-methylephedrinium bromide as phase transfer catalysts in 
reduction of acetophenone to sec-phenethyl alcohol 
In a qualitative experiment, the comparison was made of the two above-named 
catalysts in the phase-transfer reduction of acetophenone to sec-phenethyl 
alcohol. The reduction reactions were carried out using 2 mol % of each 
catalyst relative to the acetophenone and employing procedures 
substantially similar to those of Example 1. The reaction catalyzed with 
N-benzyl-N,N-bis(2-hydroxyethyl)cocoammonium chloride finished after about 
100 minutes while the reaction catalyzed with 
(-)-N-dodecyl-N-methylephedrinium bromide required about 150 minutes. This 
demonstrates that the superior catalytic activity of 
N-benzyl-N,N-bis(2-hydroxyethyl)cocoammonium chloride is not limited to 
aliphatic carbonyl compounds.