Reduction of carboxylic acid halides to aldehydes

Carboxylic acid halides are reduced to the corresponding aldehydes using zinc borohydride or cadmium borohydride as the reducing agent.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
The invention relates to a process for the reduction of carboxylic acid 
halides to aldehydes and to a reagent for the reduction. 
2. Description of the Prior Art 
A widely used process for the catalytic reduction of carboxylic acid 
chlorides to the corresponding aldehydes is the Rosenmund reduction. In 
this process, carboxylic acid chlorides are hydrogenated using a suitable 
catalyst, usually 5% palladium on barium sulfate, poisoned with a mixture 
of quinoline and sulfur to prevent further reduction to the alcohol. This 
process has the economic disadvantage that pressure equipment is required. 
An additional disadvantage is that certain functional groups other than 
the acid chloride group are reduced: for example, nitro groups are reduced 
to amino groups. 
Most hydride reducing agents reduce carboxylic acid chlorides to the 
corresponding alcohols. However, at very low temperatures, for example 
-80.degree. C. to -70.degree. C., lithium tri-t-butoxyaluminum hydride and 
sodium borohydride may be used to reduce acid chlorides to the 
corresponding aldehydes. Certain complex hydride reducing agents can be 
used for the reduction of specific acid chlorides to aldehydes; for 
example, sodium trimethoxyborohydride reduces most acid chlorides to the 
corresponding aldehydes. Certain complex hydride reducing agents can be 
used for the reduction of specific acid chlorides to aldehydes; for 
example, sodium trimethoxyborohydride reduces most acid chlorides to the 
corresponding alcohol, but reduces triacetylshikimic acid chloride to the 
corresponding aldehyde. 
SUMMARY OF THE INVENTION 
We have now found a new method of reducing carboxylic acid halides, 
especially chlorides, to give the corresponding aldehyde, and a new 
reagent capable of performing this reduction. 
The present invention provides a process for the reduction of a carboxylic 
acid halide to the corresponding aldehyde, which comprises reducing the 
acid halide using zinc borohydride or cadmium borohydride as reducing 
agent. 
The reducing agent is suitably used in the form of a solution prepared by 
mixing a solution or suspension of a zinc or cadmium salt with a solution 
or suspension of sodium borohydride. The invention therefore also provides 
a process for the reduction of a carboxylic acid halide to the 
corresponding aldehyde, which comprises reducing the acid halide using 
zinc or cadmium borohydride produced in situ. 
Preferably the acid halide is an acid bromide or, especially, an acid 
chloride. 
The alkali metal borohydride may be lithium, sodium or potassium 
borohydride and is preferably potassium or sodium borohydride. Sodium 
borohydride is most preferred. 
The cadmium halide may be cadmium fluoride, chloride, bromide or iodide and 
is advantageously cadmium chloride or cadmium bromide. Cadmium chloride is 
most preferred. 
Cadmium borohydride is a novel compound and this invention also relates to 
cadmium borohydride per se. 
Preferably a solution of cadmium borohydride is prepared by the reaction of 
cadmium chloride with sodium borohydride in a solvent system which is 
capable of dissolving at least small quantities of the reactants. Complete 
solubility of the reactants is not required. Since cadmium chloride and 
sodium borohydride are relatively insoluble in many common solvents, a 
mixture of solvents is generally required. Aprotic, polar solvents are 
required, but these need not be dried as the reaction producing cadmium 
borohydride and the subsequent reaction with an acid halide will proceed 
in the presence of traces of water. A solvent mixture of acetonitrile with 
a co-solvent, for example diglyme, hexamethylphosphoramide or, preferably, 
diethylformamide, has proved to be especially useful. 
The reduction process of the invention may, if the acid halide to be 
reduced is a liquid, be carried out in the absence of a solvent. For 
example: solid zinc borohydride may be added to the liquid acid halide. 
Preferably however, an aprotic polar solvent or mixture of such solvents 
is used such as those described above. 
Suitably a solution of the reducing agent, for example cadmium borohydride 
in a mixture of solvents, is prepared, and a solution of the acid halide 
in one or more of the solvents present in the mixture is added. 
To prepare a solution of the reducing agent, preferably a slight excess of 
one of the reagents is used. For example, 5 to 10% molar excess of a 
cadmium or zinc salt may be added to sodium borohydride. Excess sodium 
borohydride may be added, but this may be undesirable as the unreacted 
sodium borohydride may affect the course of the subsequent reduction 
reaction, for example, by increasing the yield of alcohol at the expense 
of the yield of aldehyde. 
One specific method of preparing the solution of cadmium borohydride is as 
follows: Cadmium chloride was recrystallized from dimethylformamide to 
give a solid adduct thought to have the empirical formula CdCl.sub.2.1.5 
DMF. One mol of this complex was added to a 1:1 mix of acetonitrile and 
dimethylformamide, and 2 mol of NaBH.sub.4 were added. The resulting 
solution contained approximately 0.14 m mol of cadmium borohydride per 
milliliter of solution. The bulk solution stored well at 0.degree. with a 
white solid separating out slowly. 
This white solid has now been shown not to be sodium chloride, suggesting 
that the cadmium borohydride reducing agent is not present as 
Cd(BH.sub.4).sub.2 per se, but may be present in a complex such as 
Na.sub.2 [CdCl.sub.2 (BH.sub.4).sub.2 ]. However this is a tentative 
theory which is not yet proven. 
When performing the reduction, suitably the reducing agent is used in 
slight molar excess over the acid halide, for example 5 to 10% molar 
excess. 
The reduction process of the invention has the advantage that, unlike many 
hydride reductions, extremely low temperatures are not required. The 
process of the invention may be performed, for example, at a temperature 
in the range of from -35.degree. C. to 0.degree. C., at which temperature 
satisfactory yields are obtained. For comparison, sodium borohydride, 
which is generally regarded as an agent for the reduction of carboxylic 
acid chlorides to alcohols, will reduce carboxylic acid chlorides to 
aldehydes, but yields comparable with those obtained using cadmium 
borohydride are only obtained at temperatures of around -80.degree. C. 
Cadmium borohydride will produce the aldehyde at temperatures of greater 
than 0.degree. C., but yields of by-products, for example the alcohol and 
the anhydride, increase with temperature. 
A further advantage of the use of cadmium borohydride as a reducing agent 
is that it appears to be relatively selective in its action. For example, 
ester groups, cyano groups, nitro groups, chlorine atoms and carbon-carbon 
double bonds are not reduced. Expensive pressure equipment is of course 
not required. The selectivity of the reduction process to halogen 
substituents other than that in the carboxy bromide group of the 
carboxylic acid bromide is particularly worthy of note. Even relatively 
reactive halogen, e.g. bromo and chloro, substituents in haloalkyl and 
arylhaloalkyl groups have been found to be unaffected by the reaction 
conditions of the process of the invention. 
The process of the invention may be used for the reduction of aromatic, 
cycloaliphatic or aliphatic acid halides. The reaction may be represented 
by the equation: 
##STR1## 
R may represent, for example, an aryl or aralkyl group, for example a 
phenyl or benzyl group; an alkyl, alkenyl or alkynyl group, suitably 
having up to 10 carbon atoms, for example an octyl group or a 1-propenyl 
group; or a cycloalkyl group, suitably having from 3 to 6 ring carbon 
atoms, for example a cyclopropyl or a cyclohexyl group. Any of the above 
groups may be substituted by one or more substituents, for example an aryl 
or cycloalkyl ring may be substituted by one or more alkyl, alkoxy, cyano, 
nitro, or alkoxycarbonyl groups or halogen atoms, and an alkyl, alkenyl or 
alkynyl group may be substituted by alkoxy, cyano or alkoxycarbonyl groups 
or halogen atoms. 
Preferably R may represent 
(i) a cyclopropyl group of formula 
##STR2## 
wherein R.sub.a and R.sub.b each represent an alkyl group having from 1 to 
6 carbon atoms, especially methyl, or a halogen atom of atomic number 
9-35, inclusive, especially a chlorine atom; or R.sub.a and R.sub.b 
together represent an alkylene group having from 2 to 6, especially 3, 
carbon atoms; or when R.sub.a represents a hydrogen atom then R.sub.b 
represents an alkenyl group having from 2 to 6 carbon atoms, especially an 
isobutenyl group, or an haloalkenyl group having from 2 to 6 carbon atoms 
and from 1 to 3 chlorine or bromine atoms, especially a mono- or 
dichlorovinyl group; R.sub.c and R.sub.d each represent an alkyl group 
having 1 to 6 carbon atoms, especially methyl, or when R.sub.c is hydrogen 
then R.sub.d is an alkenyl group having from 2 to 6 carbon atoms, 
especially an isobutenyl group, or an haloalkenyl group having from 2 to 6 
carbon atoms and from 1 to 3 chlorine or bromine atoms, especially a mono- 
or dichlorovinyl group; or R.sub.c and R.sub.d together represent an 
alkylene group having from 2 to 6, especially 3, carbon atoms; or 
(ii) a benzyl group of formula 
##STR3## 
wherein Z represents a halogen atom of atomic number 9-35, inclusive, 
preferably a chlorine atom, or an alkoxy group of 1 to 4 carbon atoms, 
e.g. methoxy, and Y represents an alkyl group of 1 to 6 carbon atoms, 
especially a branched chain group such as an isopropyl group. 
The process of the invention may be usefully applied in the preparation of 
aldehydes containing cyclopropyl groups. Certain aldehydes are useful in 
the synthesis of biologically active molecules, for example of the 
pyrethroid ester type from 3-phenoxybenzaldehyde.

The following Examples illustrate the invention. 
EXAMPLE 1 
Preparation of Cadmium Borohydride Solution 
Cadmium chloride was recrystallized from dimethylformamide; it is thought 
that this solid has the empirical formula CdCl.sub.2.1.5 DMF. One mol of 
this complex was added to a 1:1 mix of acetonitrile and dimethylformamide, 
and 2 mol of NaBH.sub.4 were added. The resulting solution contained 
approximately 0.14 m mol of Cd(BH.sub.4).sub.2 per milliliter of solution. 
The bulk solution stored well at 0.degree. C., with white solid NaCl 
separating out slowly. 
EXAMPLE 2 
This Example illustrates the improved yields obtained in the reduction of a 
range of carboxylic acid chlorides to the corresponding aldehydes using 
cadmium borohydride as reducing agent. 
A solution of NaBH.sub.4 (0.76 g) in dimethylformamide (5 ml) and 
acetonitrile (60 ml) was added over 10 minutes to a stirred suspension of 
4.6 g (25 m mol) CdCl.sub.2 in acetonitrile (25 ml) at 0.degree. C. The 
mixture was stirred for a further 10 minutes at 0.degree. to 3.degree. C. 
and then cooled to -35.degree. C. A solution of 20 m mol acid chloride in 
20 ml acetonitrile was added over a quarter of an hour. After stirring for 
a further 10 minutes, the temperature was allowed to rise to room 
temperature and the mixture was poured onto 2 N HCl (50 ml) and ice (50 
g). 
The aldehyde produced was isolated as its hydrazone by adding a saturated 
solution of 2,4-dinitrophenylhydrazine (20 ml) to the acidified solution. 
After warming over a steam bath, the yellow/orange precipitate of the 
2,4-dinitrophenylhydrazine of the aldehyde was filtered off. 
The results for various starting materials are listed in the following 
table, which also lists, for comparison, results obtained using sodium 
borohydride alone (i.e. without addition of CdCl.sub.2) under the same 
reaction conditions. The comparison results show that in general, yields 
obtained using cadmium borohydride are approximately double the yields 
obtained using sodium borohydride. 
__________________________________________________________________________ 
2,4-dinitrophenylhydrazone of the 
Resulting Aldehyde 
Using NaBH.sub.4 (for 
Using Cd(BH.sub.4).sub.2 
comparison only) 
% Yield % Yield 
(calculated (calculated 
on starting on starting 
Starting acid M.P. acid 
Acid Chloride chloride) 
(.degree.C.) 
chloride) 
__________________________________________________________________________ 
##STR4## 62 176-177 
32 
##STR5## 50 157-159 
23 
##STR6## 24 165-166 
7.5 
##STR7## 74 124-128 
43.6 
##STR8## 61 25 
##STR9## 81 185-187 
40.5 
CH.sub.3 . (CH.sub.2).sub.16 . CO . Cl 
High yield of polymer formed 
from aldehyde 
__________________________________________________________________________ 
EXAMPLE 3 
This Example illustrates the yields obtained in the cadmium borohydride 
reduction of a range of aromatic and aliphatic acid chlorides, many 
containing substituents sensitive to other reducing agents. 
Seventy-six mg (2 m mol) NaBH.sub.4 were dissolved in 10 ml acetonitrile 
and 0.35 ml hexamethylphosphoramide. Three hundred and seventy mg cadmium 
chloride recrystallized from dimethylformamide were added; this amount 
corresponded to 1 m mol assuming a molecular formula of CaCl.sub.2.2.5 
DMF. The reaction mixture was cooled to -10.degree. C. to -5.degree. C., 
and 2 m mol acid chloride in 2-3 ml acetonitrile were added rapidly and 
the solution stirred well for 5 minutes. Dilute HCl was added to decompose 
excess reducing agent. Excess 2,4-dinitrophenylhydrazine solution was 
added and the reaction mixture was heated on a water bath for a few 
minutes to complete the reaction. The precipitated 
2,4-dinitrophenylhydrazone was filtered, washed and dried; in many cases, 
satisfactory purity was obtained without recrystallization. The results 
are shown in the following table. 
______________________________________ 
2,4-dinitrophenylhydrazone of the 
Resulting Aldehyde 
% Yield 
(calculated 
on starting 
acid Literature 
Starting Acid Chloride 
chloride M.P. (.degree.C.)* 
M.P. (.degree.C.)* 
______________________________________ 
Benzoyl chloride 
76 241-242 237 
(acetic 
acid) 
4-methylbenzoyl chloride 
89 238-240 233-234 
4-chlorobenzoyl chloride 
74 272 270-271 
(ethanol) 
4-nitrobenzoyl chloride 
71 317-318 320 
(xylene) 
4-methoxybenzoyl chloride 
63 251-252 253-254 
(acetic 
acid) 
4-cyanobenzoyl chloride 
67 307-308 295-298 
(acetic (acetic 
acid) acid) 
2-methylbenzoyl chloride 
60 190-192 190-193 
2-bromobenzoyl chloride 
62 199-200 203 
(xylene) 
2-methoxycarbonylbenzoyl 
52 242-243 -- 
chloride (xylene) 
trans-cinnamoyl chloride 
71 253-254 255 
acid) 
phenylacetyl chloride 
58 115-117 125-126 
(ethanol/ (ethanol/ 
benzene) benzene) 
octanoyl chloride 
56 103 106 
(ethanol) 
crotonyl chloride 
54 182-184 184-185 
(ethyl 
acetate/ 
ethanol) 
pivaloyl chloride 
32 209-210 210 
(ethyl 
acetate/ 
ethanol) 
______________________________________ 
*The solvent used for recrystallization of the 2,4dinitrophenyl-hydrazine 
if recrystallization was performed, is shown in brackets. 
EXAMPLE 4 
Carboxylic acid bromides were reduced to the corresponding aldehydes by the 
following procedure. A solution of sodium borohydride (0.76 g) in 
dimethylformamide (5 ml) and acetonitrile (60 ml) was added over 10 
minutes to a stirred suspension of cadmium chloride (4.6 g, 25 m mol) in 
acetonitrile (25 ml) at 0.degree. C. The mixture was stirred for a further 
10 minutes at 0.degree. to 3.degree. C. and then cooled to -35.degree. C. 
A solution of the carboxylic acid bromide (20 m mol) in acetonitrile was 
added over a quarter of an hour. After stirring for a further 10 minutes, 
the temperature was allowed to rise to room temperature, and the mixture 
was poured onto 2 N HCl (50 ml) and ice (50 g). 
The aldehyde produced was isolated as its hydrazone by adding a saturated 
solution of 2,4-dinitrophenylhydrazine (200 ml) to the acidified solution. 
After warming over a steam bath, the yellow/orange precipitate of the 
2,4-dinitrophenylhydrazone was filtered off. 
The results obtained are given in the following table: 
______________________________________ 
2,4-dinitrophenylhydrazone 
of the resulting aldehyde 
% Yield 
(based on Melting 
starting Point 
Starting Acid Bromide 
acid bromide) 
(0.degree. C.) 
______________________________________ 
##STR10## 45 158.degree.-159.degree. C. 
##STR11## 10 165.degree.-166.degree. C. 
##STR12## 80 241.degree.-242.degree. C. 
______________________________________