Process for the preparation of substituted pyridines via 1-aza-1,3-butadienes and the 1-aza-1,3-butadiene intermediates

Process for the preparation of substituted pyridines by allowing 1-aza-1,3-butadienes to react, in the presence of a catalytic amount of secondary amine and acid, with an aldehyde or ketone, and new 1-aza-1,3-butadienes which are used in this process. Said pyridines can be obtained in high yield in a simple process with a short reaction time. The 1-aza-1,3-butadiene can, if so desired, be prepared in situ from an imine and an aldehyde.

The invention relates to a process for the preparation of a substituted 
pyridine by reaction of a 1-aza-1,3-butadiene. 
A process of this type for the preparation of pyridines is disclosed by 
Komatsu et al. (J. Org. Chem. 49, pp. 2691-2699 (1984)). They prepare 
asymmetric 3,5-substituted pyridines by allowing 1 equivalent of enamine 
and 1 equivalent of imine to react to form a 1-aza-1,3-butadiene. This 
product then reacts in the course of 20-24 hours at 200.degree. C. with 
another enamine to form an asymmetrically substituted pyridine. The yield 
varies, depending on the substituents, between 23% and 73%. 
Symmetrical 3,5-substituted pyridines are prepared by allowing 2 
equivalents of enamine to react in the presence of acid at 200.degree. C. 
for 9 hours with 1 equivalent of imine. This gives pyridines in a yield, 
depending on the substituents, of 67 to 87%. In this case the 
1-aza-1,3-butadiene is formed in situ from the enamine and the imine. 
This preparation process has various disadvantages, The production of 
symmetrical pyridines proceeds via a 3-step synthesis, that is to say the 
synthesis of, respectively, the imine, the enamine and the pyridine. 
Asymmetrically substituted pyridines are prepared via a 4-step synthesis, 
that is to say synthesis of, respectively, the imine, the enamine, the 
1-aza-1,3-butadiene and the pyridine. The reaction time for the formation 
of the pyridine is long. The enamine is usually prepared by reaction of a 
secondary amine with an aldehyde. However, this preparation frequently 
results in low yields, especially if the process is carried out using 
reactive aldehydes which are not sterically hindered. Problems in the 
preparation of enamines are described, inter alia, in Whitesell and 
Whitesell (Synthesis, July 1983, page 517-536). They give a yield of 26% 
for the formation of the enamine from acetaldehyde and 
N-butyl-N-isobutylamine. They explain this as follows: "The low yield in 
the preparation of the enamine from acetaldehyde described above was very 
probably the consequence of the occurrence of competitive condensation 
reactions and is typical of the results to be expected in the use of 
reactive aldehydes which are not sterically hindered." 
In the preparation of the enamine, equivalent amounts of secondary amine 
and aldehyde are used. For the formation of 1 equivalent of pyridine, 2 
equivalents of enamine, so also 2 equivalents of secondary amine, are 
needed. Since secondary amines are often expensive, it makes the reaction 
economically unattractive. The fact that the preparation of the enamine 
frequently proceeds with a low yield, as a result of which an 
unnecessarily large amount of secondary amine and aldehyde are consumed, 
does not make the reaction economically attractive either. 
The object of the invention is to avoid the abovementioned disadvantages. 
This is achieved according to the invention in that a pyridine according to 
formula 1 
##STR1## 
where R.sub.1 may be H or R.sub.1 and R.sub.3 can independently be chosen 
from (cyclo)alkyl, alkenyl, aryl, carboxyalkyl, carboxyaryl, aryloxy, 
alkoxy, arylthio, arylsulphonyl, NR'R" with 1-20 C-atoms, and halogens, 
where R' and R" can independently be chosen from H, (cyclo)alkyl and aryl, 
and R.sub.2 can be chosen from H, aryl, alkenyl, and (cyclo)alkyl with 
1-20 C-atoms, and only 1 of the groups R.sub.1 and R.sub.2 may be H, 
R.sub.4 is chosen from H, (cyclo)alkyl, aryl, carboxyalkyl and carboxyaryl 
with 1-20 C-atoms or R.sub.3 and R.sub.4 form together with the C-atoms to 
which they are attached a cycloalkyl-group with 4-8 C-atoms, is formed by 
allowing the 1-aza-1,3-butadiene according to formula 2 
##STR2## 
where R.sub.5 is a OH, alkyl, aryl or alkoxy group with 1-20 C-atoms and 
R.sub.1 and R.sub.2 have the meaning described above, to react, in the 
presence of a catalytic amount of secondary amine and acid, with an 
aldehyde or ketone according to formula 3 
##STR3## 
where R.sub.3 and R.sub.4 have the meaning described above. 
R.sub.1, R.sub.2, R.sub.3 and R.sub.4 usually contain 1-20 C atoms and may 
optionally be substituted. Possible substituents on R.sub.1, R.sub.2, 
R.sub.3 and R.sub.4 are, for example, halogen, --OH, --SH, (cyclo)alkyl, 
aryl, aryloxy, alkoxy, carboxyalkyl, carboxyaryl, NO.sub.2, SO.sub.2 and 
NR'R", where R' and R" can independently be chosen from H, alkyl and aryl. 
R.sub.5 is usually an alkyl or aryl group having 1-20 C atoms, such as, 
for example, tertiary butyl, isopropyl and benzyl, tertiary butyl being 
preferred, or an hydroxy group or an alkoxy group with 1-20 C atoms which 
may be unsaturated or aromatic such as for example (chloro)allyl. 
The molar ratio of 1-aza-1,3-butadiene to aldehyde or ketone which is used 
in this reaction is not critical and is preferably between 1:1 and 1:3. 
Symmetrically substituted pyridines according to formula 4 
##STR4## 
can be formed by allowing the imine according to formula 5 
##STR5## 
where R.sub.2 and R.sub.5 have the abovementioned meaning, to react, in 
the presence of a catalytic amount of secondary amine and acid, with an 
aldehyde according to formula 3, where R.sub.4 is hydrogen and R.sub.3 has 
the abovementioned meaning. It is assumed that the 1-aza-1,3-butadiene is 
formed in situ and immediately further reacts to give a symmetrically 
substituted pyridine. The invention also relates to this direct process of 
preparing symmetrical pyridines. 
The 1-aza-1,3-butadiene can also be prepared by allowing an amine R.sub.5 
--NH.sub.2 wherein R.sub.5 has the above mentioned meaning to react with 
an alpha, beta-unsaturated aldehyde according to formula 6 
##STR6## 
where R.sub.1 and R.sub.2 have the abovementioned meaning, with the 
proviso that when R.sub.5 represents an alkyl or aryl group R.sub.2 is not 
H. After the addition of an aldehyde or ketone according to formula 3 and 
a catalytic amount of secondary amine and acid, pyridines are formed. The 
reaction with ketones is preferentially performed with amines with R.sub.5 
is hydroxy or alkoxy. 
The ratio between the various reactants can vary. If formation of 
symmetrical pyridines from 1-aza-1,3-butadiene formed in situ is opted 
for, a minimum of 2 equivalents of the aldehyde according to formula 3 per 
equivalent of imine according to formula 5 is needed, on the basis of the 
reaction mechanism, to achieve optimum results. Preferably, between 2 and 
4 equivalents are added. 
The amount of secondary amine can be chosen within wide limits. It has been 
found that higher concentrations of secondary amine usually produce higher 
yields. However, secondary amines are frequently expensive. When 
determining the amount of secondary amine, economic considerations also 
play a role, in addition to yield considerations, Preferably, the molar 
ratio of aldehyde:secondary amine is chosen between 5:1 and 15:1. Many 
secondary amines are suitable for use as catalyst. Cyclic amines, in 
particular piperidine, are preferred. 
The choice of the acid is not critical. Suitable acids are, for example, 
inorganic acids, carboxylic acids or sulphonic acids, such as hydrochloric 
acid, acetic acid and p-toluenesulphonic acid. The molar ratio of 
amine:acid can vary within wide limits and is usually chosen between 0.4 
and 50. 
If the 1-aza-1,3-butadiene is prepared from an amine and an 
alpha,beta-unsaturated aldehyde, the molar ratio of amine:unsaturated 
aldehyde is generally chosen around 1:1. Usually, a small excess of amine 
(between 1.0 and 1.2 equivalents per equivalent of the unsaturated 
aldehyde) is added. In theory, equal amounts of 1-aza-1,3-butadiene and 
aldehyde or ketone are needed for the formation of the pyridine from 
1-aza-1,3-butadiene and aldehyde or ketone. In practice, an excess of 
aldehyde or ketone is usually added. 
The reaction temperature can vary within wide limits. Usually said 
temperature is chosen between 100 and 300.degree. C. A reaction 
temperature between 180 and 220.degree. C. is preferred. In this 
temperature range the reaction is complete within 2 hours in virtually all 
cases. 
It has been found that the process according to the invention provides the 
following advantages. Substituted pyridines can be prepared in a simpler 
process, with fewer reaction steps, by direct use of the readily 
accessible aldehyde or ketone, instead of the enamine, which is sometimes 
difficult to prepare. As a result, only a catalytic amount of secondary 
amine is required. Moreover, the overall yield relative to the aldehyde or 
ketone increases appreciably. The reaction time for the pyridine formation 
is appreciably reduced. 
A number of pyridines occur in natural products. The invention provides a 
process with which substituted pyridines, some of which are new, can be 
prepared in a simple manner. These pyridines can be used in various 
fields. 
Alkylpyridines can, for example, be used as precursors for 
pyridinemonocarboxylic and -dicarboxylic acids, which show a direct 
relationship with nicotine derivatives. 
The invention also relates to the new compounds having the general formula 
##STR7## 
where R.sub.1 is H and R.sub.2 is ethyl, isopropyl, n-butyl, (cyclo)alkyl 
having 5-20 C atoms, alkoxy having 1-20 C atoms, a thioalkyl, thioaryl, 
alkylamino or arylamino group having 1-20 C or atoms phenyl substituted 
with hydroxy, (cyclo)alkyl having 1-5 C atoms, halogen, or where R.sub.2 
is H and R.sub.1 is n-propyl, alkyl having 4-20 C atoms, alkoxy having 
2-20 C atoms, thioalkyl, alkylamino or arylamino group having 1-20 C atoms 
or phenyl optionally substituted with hydroxy, (cyclo)alkyl having 1-5 C 
atoms, alkoxy having 1-5 C atoms, halogen, or where R.sub.1 and R.sub.2 
each independently represent (cyclo)alkyl having 4-20 C atoms, alkoxy 
having 2-20 C atoms, halogen, a thioalkyl, thioaryl, alkylamino or 
arylamino group having 1-20 C atoms or phenyl optionally substituted with 
hydroxy, (cyclo)alkyl having 1-5 C atoms, alkoxy having 1-5 C atoms, 
halogen and the new compounds having the general formula 
##STR8## 
where R.sub.1 is H and R.sub.2 is (cyclo)alkyl having 2-20 C atoms, 
alkenyl having 3-20 C atoms, alkoxy having 1-20 C atoms, a thioalkyl, 
thioaryl, alkylamino or arylamino group having 1-20 C atoms or phenyl 
substituted with hydroxy, (cyclo)alkyl having 1-5 C atoms, alkoxy having 
2-5 C atoms, halogen or where R.sub.2 is H and R.sub.1 is (cyclo)alkyl 
having 2-20 C atoms, alkoxy having 2-20 C atoms, alkenyl having 2-20 C 
atoms, a thioalkyl, thioaryl, alkylamino or arylamino group having 1-20 C 
atoms or phenyl optionally substituted with hydroxy, (cyclo)alkyl having 
1-5 C atoms, alkoxy having 1-5 C atoms, halogen or where R.sub.1 and 
R.sub.2 each independently represent (cyclo)alkyl having 2-20 C atoms, 
alkoxy having 1-20 C atoms, alkenyl having 2-20 C atoms, halogen, a 
thioalkyl, thioaryl, alkylamino or arylamino group having 1-20 C atoms or 
phenyl optionally substituted with hydroxy, (cyclo)alkyl having 1-5 C 
atoms, alkoxy having 1-5 C atoms, halogen, and the new compounds having 
the general formula 
##STR9## 
where R.sub.1 is H and R.sub.2 is (cyclo)alkyl having 2-20 C atoms, 
alkenyl having 5-20 C atoms, alkoxy having 1-20 C atoms a thioalkyl, 
thioaryl, alkylamino or arylamino group having 1-20 C atoms or phenyl 
substituted with hydroxy, (cyclo)alkyl having 1-5 C atoms, alkoxy having 
1-5 C atoms, halogen or in which R.sub.2 is H and R.sub.1 is (cyclo)alkyl 
having 3-20 C atoms, alkenyl having 2-7 C atoms, alkoxy having 1-20 C 
atoms, a thioalkyl, thioaryl, alkylamino or arylamino group having 1-20 C 
atoms or phenyl optionally substituted with hydroxy, (cyclo)alkyl having 
1-5 C atoms, alkoxy having 1-5 C atoms, halogen or where R.sub.1 and 
R.sub.2 each independently represent (cyclo)alkyl having 3-20 C atoms, 
alkenyl having 2-20 C atoms, alkoxy having 1-20 C atoms, a thioalkyl, 
thioaryl, alkylamino or arylamino group having 1-20 C atoms or phenyl 
optionally substituted with hydroxy, (cyclo)alkyl having 1-5 C atoms, 
alkoxy having 1-5 C atoms, halogen, and the new compounds having the 
general formula 
##STR10## 
where R.sub.1 is H and R.sub.2 is (cyclo)alkyl having 2-20 C atoms, 
alkenyl having 2-20 C atoms, alkoxy having 1-20 C atoms, halogen, a 
thioalkyl, thioaryl, alkylamino or arylamino group having 1-20 C atoms or 
phenyl substituted with hydroxy, (cyclo)alkyl having 1-5 C atoms, alkoxy 
having 1-5 C atoms, halogen, with the proviso that phenyl is not 
substituted in the p-position with methyl, isopropyl, methoxy, Cl or Br, 
or where R.sub.2 is H and R.sub.1 is (cyclo)alkyl having 3-20 C atoms, 
alkoxy having 1-20 C atoms, alkenyl having 2-20 C atoms, halogen, a 
thioalkyl, thioaryl, alkylamino or arylamino group having 1-20 C atoms or 
phenyl optionally substituted with hydroxy, (cyclo)alkyl having 1-5 C 
atoms, alkoxy having 1-5 C atoms, halogen, or where R.sub.1 and R.sub.2 
each independently represent (cyclo)alkyl having 2-20 C atoms, alkenyl 
having 2-20 C atoms, alkoxy having 1-20 C atoms, halogen, a thioalkyl, 
thioaryl, alkylamio or arylamino group having 1-20 C atoms or phenyl 
optionally substituted with hydroxy, (cyclo)alkyl having 1-5 C atoms, 
alkoxy having 1-5 C atoms, halogen with the proviso that R.sub.1 and 
R.sub.2 are not at the same time given by R.sub.1 =C.sub.2 H.sub.5 or 
C.sub.3 H.sub.7 and R.sub.2 = a phenylgroup in the p-position substituted 
with CH.sub.3, OCH.sub.3, F, Cl or Br, and the new compounds having the 
general formula 
##STR11## 
where R is (cyclo)alkyl with 1-20 C atoms and R.sub.1 and R.sub.2 each 
independently represent H, (cyclo)alkyl having 1-20 C atoms, alkoxy having 
1-20 C atoms, alkenyl having 2-20 C atoms, halogen a thioalkyl, thioaryl, 
alkylamino or arylamino group having 1-20 C atoms or phenyl optionally 
substituted with hydroxy, (cyclo)alkyl having 1-5 C atoms, alkoxy having 
1-5 C atoms, halogen, with the proviso that R, R.sub.1 and R.sub.2 are not 
at the same time given by R is H and R.sub.2 is phenyl or phenyl in the 
p-position substituted with methyl, methoxy or halogen, or R is CH.sub.3, 
R.sub.1 is CH.sub.3 and R.sub.2 is phenyl; These compounds are formed as 
an intermediate in the process according to the invention. 
Alkyl, alkenyl or aryl groups may optionally be substituted with the 
abovementioned substituents.

The invention is further elucidated by means of the following examples, 
without being restricted by these. 
The NMR data are given as follows. The shift is indicated in ppm downfield 
with respect to TMS. The multiplicity is indicated as s (singlet), d 
(doublet), t (triplet), q (quartet), sept. (septet), m (multiplet) and b 
(broad signal). Aromatic protons are given as pyr. (protons on pyridine 
ring) and Ph. (protons on phenyl ring). 
EXAMPLE I 
Preparation of 1-tert-butyl-4-phenyl-1-aza-1,3-butadiene 
20.3 grams of t-butylamine (0.28 mol) was metered over a period of 16 
minutes to 33.0 grams of cinnamaldehyde (0.25 mol) during stirring and 
cooling. The mixture was left to stand overnight at room temperature. 150 
ml of butanone was then added to the crude reaction mixture to enable the 
water formed during the reaction to be evaporated azeotropically. The 
mixture was evaporated on a rotary evaporator. The residue consisted of 
45.6 grams of product having a purity of 98%. Yield 96%. 
.sup.1 H NMR: .delta.=1.29 ppm, s, 9H, 3 CH.sub.3 .delta.=6.80 ppm, s (b), 
and .delta.=6.89 ppm, s (b), 2H, 2CH.dbd..delta.=7.10-7.55 ppm, m, 5H, Ph. 
.delta.=7.93 ppm, t, 1H, CH.dbd.N 
Preparation of 3-methyl-4-phenylpyridine, from 
1-tert-butyl-4-phenyl-1-aza-1,3-butadiene and propanal 
3.7 grams (20 mmols) of the 1-aza-1,3-butadiene prepared above, 3.5 grams 
of propanal (60 mmols), 0.7 gram of piperidine (8.2 mmols), 4.4 grams of 
toluene (solvent) and 1.0 gram of a solution of 1.2 grams of acetic acid 
in 48.8 grams of toluene (0.4 mmol of acetic acid) were added together in 
a Cr-Ni steel autoclave with a capacity of about 15 ml. The latter was 
heated for 2 hours in an oil bath at a temperature of 200.degree. C. After 
2 hours the reaction mixture was cooled in air. The not optimized yield of 
3-methyl-4-phenylpyridine was 34% (GC analysis). The reaction mixture was 
purified by means of a fractional distillation, by which means product 
having a purity of 86% was obtained. Further purification took place by 
dissolving the distillate in hexane and by passing HCl gas through this 
solution, as a result of which the pyridine HCl salt precipitated. The 
salt was filtered off. A dilute sodium hydroxide solution was then added, 
after which the aqueous solution was extracted with dichloromethane. After 
evaporating off the dichloromethane, product having a purity of 98.8% was 
obtained. 
.sup.1 H NMR: .delta.=2.23 ppm, s, 9H, 3 CH.sub.3 .delta.=7.03 ppm, d, 1H, 
pyr. .delta.=7.1-7.5 ppm, m (b), 5H, Ph. .delta.=8.38 ppm, d, 2H, pyr. 
EXAMPLE II 
Preparation of the imine of t-butylamine and formaldehyde 
(t-butylmethyleneimine as triazine trimer) 
295.0 grams of t-butylamine (4.0 mols) was metered to 120.0 grams of 
paraformaldehyde (4.0 mols), with cooling. 1/3 of the amine was added in a 
single amount. The stirrer was then started. The remainder of the amine 
was added over a period of 11/4 hours, after which the mixture was stirred 
for a further 1/2 hour at room temperature. The crude reaction mixture was 
transferred to a separating funnel, in which said mixture separated in the 
course of about 2 hours into an aqueous phase and a turbid organic phase. 
The organic phase was filtered through filter earth. The clear filtrate, 
327.6 grams, consisted of 98% pure imine (in the form of triazine trimer). 
Yield 94%. 
Preparation of 3,5-dimethylpyridine from t-butylmethyleneimine and propanal 
211.8 grams of the t-butylmethyleneimine prepared above (98% pure, 2.44 
mols), 424.5 grams of propanal (7.32 mols), 292.8 grams of toluene 
(solvent), 76.1 grams of piperidine (0.9 mol) and 103.6 grams of acetic 
acid (1.73 mols) were mixed with cooling in an ice/water bath while being 
stirred. Piperidine and acetic acid were added in small portions in 
connection with the release of heat. The mixture was transferred to an 
autoclave and heated at 200.degree. C. for 3 hours (heating-up time about 
45 min.). The reaction mixture was cooled to room temperature. It was then 
washed with 400 grams of a 20% (wt) NaOH solution in water. The aqueous 
phase contained no 3,5-dimethylpyridine. The organic phase contained 100.0 
grams of product (not optimized yield 38.3%). The volatile components were 
distilled off from the organic phase under atmospheric pressure through a 
column having 20 actual plates. The residue was distilled under vacuum 
through a column having 20 actual plates. This resulted in 78.9 grams of 
3,5-dimethylpyridine having a purity of 98% (distillation yield 79%, 
overall yield 30.2%). Boiling point 104.degree.-107.degree. C. (102 mm 
Hg). In this case the 1-aza-1,3-butadiene was formed in situ from the 
imine and the aldehyde, after which the pyridine formation took place. 
.sup.1 H NMR: .delta.=2.28 ppm, s, 6H, 2 CH.sub.3 .delta.=7.23 ppm, m, and 
.delta.=8.75 ppm, m, 3H, pyr. 
EXAMPLE III 
Preparation of 3,5-dimethylpyridine from t-butylmethyleneimine and propanal 
1.7 grams of the t-butylmethyleneimine prepared in Example II (20 mmols), 
3.5 grams of propanal (60 mmols), 0.8 gram of piperidine (9.4 mmols), 6.1 
grams of toluene (solvent) and 1.0 gram of a solution of 1.2 grams of 
acetic acid in 48.8 grams of toluene (0.4 mmol of acetic acid) were added 
together in a Cr--Ni steel autoclave with a capacity of about 15 ml. The 
latter was heated for 2 hours in an oil bath at a temperature of 
200.degree. C. After 2 hours the reaction mixture was cooled in air. The 
yield of 3,5-dimethylpyridine was 50% (GC analysis). 
EXAMPLE IV 
Preparation of 3,5-diethylpyridine from t-butylmethyleneimine and butanal 
1.7 grams of the t-butylmethyleneimine (20 mmols) prepared in Example II, 
4.3 grams of butanal (60 mmols), 0.7 gram of piperidine (8.2 mmols), 5.6 
grams of toluene (solvent) and 1.0 gram of a solution of 1.2 grams of 
acetic acid in 48.8 grams of toluene (0.4 mmol of acetic acid) were added 
together in a Cr--Ni steel autoclave with a capacity of about 15 ml. The 
latter was heated for 2 hours in an oil bath at a temperature of 
200.degree. C. After 2 hours the reaction mixture was cooled in air. The 
not optimized yield of 3,5-diethylpyridine was 55% (GC analysis). The 
crude product was purified by means of vacuum distillation. Boiling point 
86.degree.-88.degree. C. (10 mm Hg), purity 84%. Further purification took 
place by precipitating the distilled product as the HCl salt in hexane. 
The salt was filtered off and then dissolved in water and the solution was 
neutralised using 33% strength by weight NaOH solution in water. The 
aqueous solution was then extracted with dichloromethane. This resulted in 
a product having a purity of 98.5%. 
.sup.1 H NMR: .delta.=1.20 ppm, t, 6H, 2 CH.sub.3 .delta.=2.58 ppm, q, 4H, 
2 CH.sub.2 .delta.=7.20 ppm, t, and 8.18 ppm, d, 3H, pyr. 
EXAMPLE V 
Preparation of 3,5-di-isopropylpyridine from t-butylmethyleneimine and 
isovaleraldehyde 
1.7 grams of t-butylmethyleneimine (20 mmols), 5.2 grams of 
isovaleraldehyde (60 mmols), 0.7 gram of piperidine (8.2 mmols), 4.7 grams 
of toluene (solvent) and 1.0 gram of a solution of 1.2 grams of acetic 
acid in 48.8 grams of toluene (0.4 mmol of acetic acid) were added 
together in each of 4 Cr--Ni steel autoclaves with a capacity of about 15 
ml. The latter were heated for variable periods in an oil bath at a 
temperature of 200.degree. C. The reaction mixtures were then cooled in 
air. The not optimized yield was 47% after 1 hour, 51% after 2 hours, 53% 
after 3 hours and 56% after 4 hours (GC analysis). The crude product was 
purified by means of distillation, which resulted in a number of fractions 
having a 3,5-di-isopropylpyridine content which varied between 10 and 80%. 
The 3,5-di-isopropylpyridine crystallized out in the fractions having a 
content higher than 38%. Product having a purity of 93% was obtained by 
filtering off. 
Melting point 36.5.degree.-38.5.degree. C. .sup.1 H NMR: .delta.=1.25 ppm, 
d, 12H, 4 CH.sub.3 .delta.=2.88 ppm, sept., 2H, 2 CH .delta.=7.28 ppm, t, 
and 8.20 ppm, d, 3H, pyr. 
EXAMPLE VI 
Preparation of the imine of t-butylamine and benzaldehyde 
36.0 grams (0.5 mol) of t-butylamine was metered to 52.2 grams of 
benzaldehyde (0.5 mol) over a period of 60 minutes during stirring. After 
all of the t-butylamine had been added, the mixture was stirred for a 
further 1 hour at room temperature. A further 14.6 grams (0.2 mol) of 
t-butylamine was then added, after which the mixture was stirred for 11/2 
hours at room temperature. The reaction mixture was transferred to a 
separating funnel and 100 ml of diethyl ether was added to allow better 
separation of the organic and the aqueous phase. The organic layer was 
dried over MgSO.sub.4. The latter was filtered off. The filtrate was 
evaporated in a rotary evaporator. This yielded 65.0 grams of product 
having a purity of 99%. Yield 82%. 
.sup.1 H NMR: .delta.=1.34 ppm, s, 9H, 3 CH.sub.3 .delta.=7.18-7.40 ppm, m, 
and 7.56-7.78 ppm, m, 5H, Ph. .delta.=8.16 ppm, s, 1H, CH.dbd.N 
Preparation of 3,5-diphenylpyridine from t-butylmethyleneimine and 
phenylacetaldehyde 
10.3 grams of the t-butylmethyleneimine prepared above (98% pure; 0.12 
mols), 51.0 grams of phenylacetaldehyde (85% pure; 0.36 mols), 13.4 grams 
of toluene (solvent), 4.52 grams of piperidine (0.053 mols) and 0.20 grams 
of acetic acid (0.003 mols) were mixed with cooling in an ice/water bath 
while being stirred. The mixture was transferred to an autoclave and 
heated at 200.degree. C. for 11/2 hours. After cooling to roomtemperature 
the separated crystals were filtered and washed with suction. After drying 
of the solid 19.0 grams of 98% pure 3,5-diphenylpyridine was obtained (The 
yield was 68% without any optimization). In this case the 
1-aza-1,3-butadiene was formed in situ from the imine and the aldehyde, 
after which the pyridine formation took place. 
.sup.1 H NMR: .delta.=7.4-7.7 ppm, m, 10H, 2 Ph .delta.=8.05 ppm, t, 1H, 
4-H .delta.=8.83 ppm, d, 2H, 2-H and 6-H 
EXAMPLE VII 
Preparation of formaldoxime (as trimer) 
64.2 grams of a solution of NaOH in water (50%; 0.802 mols) was added to a 
stirred solution of 66.1 grams of hydroxylamine sulfate (0.805 mols) in 
134.1 grams of water with cooling (t .perspectiveto.25.degree. C.). Then, 
a solution of 22.2 grams of formaldehyde (0.74 mols) in 37.8 grams of 
water was added, immediately followed by the addtion of 100 ml of ether. 
After separation of the two layers, the water phase was extracted 3 times 
with ether. The combined organic phases were dried (CaCl.sub.2) and the 
solvent was evaporated in vacuum. The residue (30.0 grams) consisted of 
97% pure formaldoxime (in the form of its trimer). Yield: 87%. 
Preparation of 3,5-dimethylpyridine from formaldoxime and propanal 
6.3 grams of the formaldoxime prepared above (97% pure; 0.14 mols), 23.2 
grams of propanal (0.4 mols), 52.2 grams of toluene (solvent), 5.24 grams 
of piperidine (0.062 mols) and 0.36 grams of piperidine. HCl salt (0.003 
mols) were mixed with cooling in an icewater both while being stirred. The 
mixture was transferred to an autoclave and heated at 200.degree. C. for 
11/2 hours. After cooling to room temperature the reaction mixture was 
analyzed. The not optimized yield of 3,5-dimethylpyridine was 26% (GC 
analysis). 
EXAMPLE VIII 
Preparation of cinnamaldehyde oxime 
53.3 grams of cinnamaldehyde (0.40 mols) was added to a solution of 39.1 
grams of hydroxylamine sulfate (0.48 mols) in 79.5 grams of water. The 
mixture was cooled in an icewater bath to 3.degree. C. Then a solution of 
17.7 grams of NaOH (0.44 mol) in 17.7 grams of water was added over a 
period of 25 minutes. The formed cinnamaldehyde oxime precipitated. The 
reaction mixture was warmed to roomtemperature and the crude product was 
filtered. After recrystallization from toluene pure cinnamaldehyde oxime 
was obtained as white crystals. Yield: 70%. 
Preparation of 4-phenyl-5,6,7,8-tetrahydroquinoline 
13.9 grams of the cinnamaldehyde oxime prepared according to the above 
described procedure (0.09 mols), 28.5 grams of cyclohexanon (0.29 mols), 
30.3 grams of toluene (solvent), 3.44 grams of piperidine (0.040 mols) and 
0.259 grams of piperidine. HCl salt (0.002 mols) were mixed with cooling 
in an icewater bath while being stirred. The mixture was transferred to an 
autoclave and heated at 200.degree. C. for 11/2 hours. After cooling to 
room temperature the mixture was analyzed. The not optimized yield of 
4-phenyl-5,6,7,8-tetrahydroquinoline was 34% (GC-analysis). 
EXAMPLE IX 
Preparation of methacroleine oxime 
32.7 grams of hydroxylamine hydrochloride (0.47 mols) was dissolved in 66.4 
grams of water. This solution was cooled in an icewater bath to 
3.degree.-5.degree. C. and 32.0 grams of methacroleine (0.45 mols) was 
added with stirring. Subsequently 35.7 grams of a solution of NaOH in 
water (50%; 0.45 mol) was added at 4.degree. C. over a period of 1 hour. 
Then the reaction mixture was brought at room temperature and extracted 
with ether. The combined organic phases were dried (MgSO.sub.4) and the 
solvent was removed under reduced pressure. The residue (36.7 grams) 
consisted of pure methacroleine oxime (93% in ether); Yield: 89%. 
Preparation of 3,5-dimethylpyridine from methacroleine oxime and propanal 
13.0 grams of the methacroleine oxime prepared according to the above 
described procedure (93% in ether; 0.14 mol), 22.0 grams of propanal (0.38 
mols), 46.5 grams of toluene (solvent), 4.93 grams of piperidine (0.058 
mols) and 0.35 grams of piperidine. HCl salt (0.003 mols) were mixed with 
cooling in an icewater bath while being stirred. The mixture was 
transferred to an autoclave and heated at 200.degree. C. for 11/2 hours. 
After cooling to room temperature the mixture was analysed. The not 
optimalized yield of 3,5-dimethylpyridine was 28% (GC-analysis). 
EXAMPLE X 
Preparation of 3,5-dimethylpyridine from O-methylformaldoxime and propanal 
8.3 grams of O-methylformaldoxime (0.14 mols), prepared according to the 
procedure of Jensen et al. (Acta Chem. Scand., 31, 28 (1977), 23.2 grams 
of propanal (0.40 mols) 52.2 grams of toluene (solvent), 5.33 grams of 
piperidine (0.063 mols) and 0.18 grams of acetic acid (0.003 mols) were 
mixed with cooling in an icewater bath while being stirred. The mixture 
was transferred to an autoclave and heated at 200.degree. C. for 11/2 
hours. After cooling to room temperature the reaction mixture was 
analysed. The not optimized yield of 3,5-dimethylpyridine was 28% (GC 
analysis).