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N-Substituted Tetrahydro-1 4-oxazines Ц A New Class of Fungicidal Compounds.

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N-Substituted Tetrahydro-l,4-oxazines - A New Class of Fungicidal Compounds
BY DR. K.-H. KONIG, DR. E.-H. POMMER, AND DR. W. SANNE
BADISCHE ANILIN- & SODA-FABRIK AG., LUDWIGSHAFEN/RHEIN (GERMANY)
Published an the occasion of the 100th anniversary of the establishment of
Badische Anilin- & Soda-Fabrik AG., on April 6th, 1965
Tetrahydro-I ,I-oxazines with large alicyclic or long alkyl groups [ *] attached to the
nitrogen exhibit good or very good fungicidal activities againsf fungus diseases of crops,
particularly against the true mildew varieties. - BY examining several hundred compounds,
the relations between chemical constitution and fungicidal action were investigated in an
attempt to find the mosf effective compounds. The factors varied were the nature, chain
length, and ring size of the N-substituent, and the nature, number, and positions of the
C-substituents on the heterocyclic system. Furthermore, the lone electron pair at the
nitrogen atom was incorporated by alkylation, formation of amine oxides or salts, or by
complexing with heavy metal salts, and the resulting changes in the fungicidal activity
were determined.
I. Introduction
Every year, fungus diseases cause great damage to crops,
and thus appreciably lower their yield. Fungal damage
in the U. S. A. in 1954 was responsible for a reduction
of 7 % or 2.8 billion dollars in the agricultural and forestry returns [I]. In Ceylon, the cultivation of coffee
beans had to be abandoned owing to the extensive incidence of leaf rust. The cultivation of tobacco in South
Africa was severely reduced by a powerful attack of
mildew. The fact that practically no winter barley is
grown in Denmark and Sweden is due to barley mildew.
European viniculture came to the brink of extinction
around 1870 following the Peronospora epidemic after
the disease had found its way here from overseas. It was
only thanks to the discovery, or rather the rediscovery,
of the Bordeaux spray that the attack was weakened in
subsequent years. Great losses were suffered by the tobacco harvest as a result of the blue mold in 1959 and
1960, especially in Germany and the neighboring countries. Practically the entire potato harvest failed in Germany in 1917 because of the fungus Phytophthora infestans, and this event was largely responsible for the socalled “turnip winter” in 1917-1918. Fungi can damage
fruit even after harvesting, for example in the citrus family, rendering the fruit unpaIatable within a few days. The
task of developing new fungicides is therefore of great
economic importance.
In comparison with the number of herbicides and insecticides,
the number o f organic compounds possessing fungicidal
activity is small. The broadest possible spectrum, good
plant tolerance, and a simple and cheap synthesis are the
essential criteria of a fungicide.
Occasionally nitrogenous compounds with long alkyl
chains exhibit considerable biological activity. Thus a
[*I Compounds of this type are the subject of German and other
patent applications.
[I J E. G. Shurvelle: The Nature and Uses of Modern Fungicides.
Burgess Publishing Comp., Minneapolis 1961, p. 30.
336
herbicidal action is shown by N-laurylhexamethylenimine, while 2-heptadecylimidazoline acetate and laurylguanidine acetate are particularly active against apple
scab ( Venturia inaequalis).
Although easy to prepare by known methods, tetrahydro1,Coxazines have not yet been tested for their plantprotecting action. 2-Phenyl-3-methylmorpholinehas
been the only biologically active oxazine to achieve importance as a drug.
11. The Preparation of Tetrahydro-1,Coxazines
1. Syntheses of the Ring System
Tetrahydro-l,4-oxazine, i.e. morpholine ( I ) , R = H, is
obtained in good yield by dehydration and cyclization of
bis-(2-hydroxyethyl)amines (Z), R = H, by sulfuric acid
[2], hydrogen halides, acid halides, or dehydrating catalysts [3] at 160-260 “C. Considerably better yields are
generally obtained and lower temperatures (80-140 “ C )
are needed when the amino hydrogen of the bis-(2hydroxyalky1)amine is replaced by a hydrocarbon group
[R H in (2)]. Moreover, ring closure is facilitated when
the carbon atoms carrying the OH-groups are tertiary or
quaternary [see ( 5 ) --f (6) ; ( 7 ) +(S)].
+
[21 L. Knorr, Ber. dtsch. chem. Ges. 16, 1267 (1883); 22, 2084
(1889); Liebigs Ann. Chem. 301, 1 (1898); L. Medurd, Bull. SOC.
chim. France 3, 1338 (1936).
[3] U.S.-Pat. 2597260 (May 20th, 1952), Armour and Co.,
inventor: R . A. Reck; German Pat. 844006 (Sept. 28th, 1950),
BASF, inventor: E. Weiss.
Angew. Chem. internat. Edit. I VoI. 4 (1965)
I NO.4
Other possibilities are the ring-closure of bis-(2-halogenoethyl) ethers (3) [4] or bis-(2-hydroxyethyl) ethers
(4), as well as the ring closure of glycols with amines [5].
FHz-CHzCl
0,
CH2- CHzCl
+
-2HC1
H2N-R
%I-R
9CH2-CH
c H~ CH;
-
(3)
+ HzN-R
CHz- CHz-OH
-0:
150-4OoOC
- 2 H,O
CH2-CH
a - R
C H -~CH,/
hydro- 1,4-oxazine, the starting material must be a 1amino-2-hydroxyethane (9) that is substituted on the
carbon atom adjacent to the nitrogen. These 1,2-amino
alcohols are prepared by base-catalysed addition of nitroalkanes containing acidic hydrogen atoms to carbonyl compounds such as formaldehyde, acetaldehyde, or
acetone, and catalytic hydrogenation of the resultant 1,2nitroalcohols, e.g. (9a) [7]. 1,2-Alkylene oxides convert
the 1,2-amino alcohols, via bis-(2-hydroxyalkyl)amines,
into 2- and/or 5-substituted tetrahydro-1,4-oxazines, for
example (10).
(41
y
+
CH3-CHZ-NO2
-
2. Introduction of Substituents at the Carbon Atoms
+ H2
Bis-(2-hydroxyalkyl)amines can be prepared by adding
ammonia or primary amines [2] to 1,Zalkylene oxides,
a wide range of the latter being available from petroleum
products. If 2 moles of the same epoxide or 1 mole each
of two different epoxides (e.g. 2,3-butylene oxide and
propylene oxide) are reacted with 1 mole of ammonia or
a primary amine, then symmetrically (5) or unsymmetrically (7) substituted bis-(2-hydroxyalk~l)aminesare
obtained, which on dehydrating cyclization yield symmetric (6) or unsymmetric (8)tetrahydro-l,4.oxazines.
-
FH3 R-NH,
H3?
HC
C
,-,H
0
7H3 p 3
R-NH-CH-CH-OH
HI?
?HI
HCyCH
0'
H-
3
HO-CHz-CH-NO2
(90)
CH3
H O - C H ~ ~ H - N H( 9~)
-
(9) + H2C-CH-CH3
+
7H3
CH- CH2- OH
H-<
'0'
CH
-P
).A
HN
CH2-CH-OH
AH3
q
H
(10)
If the amine t o be cyclized carries two substituents on
different carbon atoms, two sterically different products are
obtained on ring closure in about equal amounts. They can
be detected by gas chromatography as, for example, in the
case of the 2,6-dialkylmorpholines.
YH3 FH3
CH - CH - OH
R-I(
3. Introduction of Substituents at the
Nitrogen Atom
CH-YH-OH
CH3 CH3
/
H2C,-CH-CHI
FH3
O
'
YH-YH-OH
CH3 CH3
-H20/
R-N
-H,O
Alkylation of the nitrogen atom in tetrahydro-l,4-oxazines by means of alkyl halides is successful with aliphatic compounds, but it is frequently unsuccessful with
alicyclic halides which are dehydrohalogenated to
cycloalkenes. It is therefore practical, particularly in the
alicyclic series, to synthesize by hydroxyalkylation witn
epoxides N-substituted amines which are then cyclized
(cf. Section 11.2), or to react a cyclic ketone with the
tetrahydro-l,4-oxazine, which is unsubstitued on the nitrogen atom, and hydrogenate the resulting enamine.
H3cHcH3
dCH3
C H2-C H - OH
R-i(
(5)
HCH3
0
H3C
( 7)
R-N'
H,C
HCH,
lo
(')
181
Substituents can in this way be introduced at positions 2
and/or 6, and, by using a symmetric epoxide, at positions
3 and 5 as well. On adding an unsymmetric 1,2-epoxide
to an amine, the epoxide ring will usually be opened in
such a way that the OH-group is attached to the carbon
atom carrying the least number of hydrogens 161. Using
the same amine, ring opening of the 1,2-alkylene oxides
becomes more difficult as the number of substituents in
the latter increases (or, in the case of epoxides with the
same number of substituents, as the symmetry of the
epoxide increases).
R
B
O
H
5R
R'
Angew. Chem. internat. Edit.
VoI. 4 (1965)
I No. 4
B
R'
O
H
- B*RB
R
0 2
- H,O
R'
For the introduction of only one substituent at position
3, or only two substituents at positions 3 and 5 of tetra[4] 0. Kamm and J . H . Waldo, J. Amer. chem. SOC.43,2225
(1921); L. H . Cretcher, J. A . Koch, and W . H . Pittenger, ibid.47,
1174 (1925).
[S] In the presence of catalysts for hydrogenation/dehydrogenation and hydrogen. See German Published Patent Application
1049864 (May 2nd, 1957), Wyandotte Chemical Corp.; Brit.
Pat. 813957 (May 8th, 1957), Jefferson Chemical Comp.
[6] K. Krussusky et al., C . R. hebd. Seances Acad. Sci. 146, 236
(1908); J. prakt. Chem. [2] 77, 84 (1908).
-
The Primary alicYclic amines (11) and (12) ~ ~ e d for
ed
the first Procedure were Prepared by the usual methods
(114
0
0
+
R-CHO
2%
A
-''
p
NHz
R'
(11)
(120)
CH-R
QZR
NH2 (12)
CHzR
[7] E. Schmidf and R . Wdkendorf, Ber. dtsch. chem. Ges. 52,
389 (1919); 55, 316 (1922).
337
3
Table I . Increase of the fungicidal action on passing from amino alcohols to the corresponding
rnorpholines (R = morpholino group; R = 2,6-dimethylmorpholino group) 1'1.
Infection of the leaves after spraying
with an x % solution of the comDound
B.p.
Compound
I
1OC/mml
x
=
0.2
0.1
180-190/1.5
1
2*
2
137-14512.0
I
***
**
173--178/1.5
1.
3
155- l60/5.0
***
.+*
190-202/1.5
0"
0'8
***
***
**
O*
5
~
1
175- 180/2.5
140--144/0.2
Cyclooctyl-R
103/0.4
nL5 = 1.4855
Cyclododecyl-R
_
5
5
5
5
-
*f
2
5
0
3
5
0'
12
4
~
-
-
---
0
1
,
1
1
-
1 50-153/0.5
195--197/1.0
3
5
***
9 1-93/0.01
Cyclooctyl-NICH~-CH(CH~)-OHlz
_
~~-
130- 142/1.3
nLs = 1.4568
Cyclooctyl-NH-CHz-CH(CHa)-OH
_
1'
--
152-160/1.s
5
-
3
1
16I-- 162/1.5
nL5 = 1.4907
I
2
**.
O*
[*I Key to Tables 1 - 5 : 0 = no infection, ranging t o 5 = total infection.
* = slight leaf damage, ranging to = * * * total damage.
Table 2. Influence of the N-substituent on the fungicidal action of 2,6-diniethyltetrahydro-1,4-oxazines
= 2,6-dimethylrnorpholino group!
(R'
Infection of the leaves after spraying
with an x % lution of the compound
B. p.
Compound
IVmml
x
= 0.2
1 0.1
0.025
1
0.006
1
0.0015
~~~
i-CgH19-R
3
98- lOO/l .O
nL5 = 1.4525
1 5
1 5
12
14
93/0.4
n g = 1.4521
**
155-160/5.0
139--142/1.3
n g = 1.4568
200-208/ I . 5
Cyclohexyl-R
74/0.4
Cycloheptyl-R
80-8 I /0.5
cyclooctyl- R
103/0.4
nks = 1.4855
Cyclododecyl-R
***
***
~- O
o* 1 0
lo I1
2
1 2
1 3
0'
O
lo
12
0
0
2
3
---
161- 162/1.5
ng = 1.4907
-
4-Methylcyclohexyl- R
132-137/1.2
0
100- 103/0.1
.I.
1
~
4-Nonylcyclohexyl- R
147- 15 1/0.2
/3-Naphthyl-R
141- 148/0.1
~
4-Cyclohexylcyclohexyl- R'
136-138/0.2
169- 17410.4
0.
129-138/0.6
1.'
170- 182/0.5
0'
184-190/0.1
0.8
1
I
I 1' ~
2
3
1
1
I 0' 0
I O* 0 I 1 1 2
-
-
Angew. Chem. internat. Edit. 1 Vol. 4(1965)
/ No. 4
[8], mainly by complete hydrogenation of the easily
available alkylphenols, followed by dehydrogenation of
the resulting alcohols to yield ketones ( I l u ) , and reductive amination of the latter. Alternatively, carbonyl
compounds were condensed with cycloalkanones, followed by hydrogenation and reductive amination of the resulting cycloalkylidenealkanones(I2a).
Some tetrahydro-1,4-oxazines, particularly those carrying
large alicyclic substituents, behave as sterically hindered
strong bases ("Hiinig bases"), and are difficult to peralkylate
with the usual reagents [*I.
111. Relations between the Chemical Constitution
and the Fungicidal Action of Tetrahydro-1,4oxazines, Their Precursors, and Analogues
For the sake of clarity, the following Tables list only the
results obtained on treating Erysiphe graminis (powdery
mildew of barlev).
Most morpholines are active against powdery mildews
(such as the mildews of cereals, cucumbers, roses, gooseberries, scorzonera, and apples), against fungi causing
plant rusts such as grain rust, against Sigafoku, a furigus
disease of banana leaves, and also against the molds
attacking citrus fruits. Some morpholines are also active
against downy mildew fuligi such as Peronospora and
Phytophthoru. The compounds included in the Tables
represent only a small fraction of the large number of
substances examined.
Table 1 shows tnat the fungicidal action is generally
stronger for tetrahydro- 1,4-nxazines than for the corresponding amino alcohols. It is immaterial whether the
amino slcohol contains one or two OH-groups. The
great influence of the N-substituent of the tetrahydro1,4-oxazine upon the fungicidal action is shown in
Table 2.
Table 3. Variation of the fungicidal action with the C-suhstituents at the
tetrahydro- 1,4-oxazine ring.
_ ,
~~
B.p.
Compound
[ "C/mm]
XI to
x6=
II
~~
Infection of the leaves after spraying
with an x % solution of the compound
x
=
0.2
1
0.1
I
0.025
1
0.006
0.0015
__
i-CI3Hz7-N
H
4
x5
x
4
_ _ _ _ _ ~ -
***
139-142/1.3
n'd = 1.4568
1 1 1- 1 12/0.1
n6s = 1.4607
4
_ _ _ - ~ * * * *** 0'
,
2
~
It.
o*
I
0
~
116/1.1
rigs= 1.4950
x
4 x3
106-l07/0.6
ngS = 1,4920
103/0.4
nLs = 1.4855
92-94/0.2
nL5 = 1.4878
109- 112/0.3
nL5 = 1.4820
__
0
1
o*
198-205/1.5
H
0
0'
2
It*
135- 136/0.8
nks = 1.4580
x4=
1
0
_
0
0.
10
__
1 1 1- 1 14/0.4
rigs= 1.4850
2
2
1
3
No. 4
3
4
~-~
1
1
~
0
3
2
2
-
1
4
1
~~0
2
5
2
_____-
~
5
I
1 1 i
3
5
I
4
-
2 17-225/0.5
Angew. Chem. internat. Edit./ VoI. 4 (1965)
~
__
163-16510.5
PI H . Schroter in Houben- We.d: Methoden der organischen
Chemie. 4th Edit., Thieme, Stuttgart 1957, Vol. 11, p. 602.
['I The quaternary tetrahydro-oxazonium salts were investigated
especially by Dr. A . Steimmig.
3
_
1
N-Alkyltetrahydro- 1,4.0xazines
5
(except
~
3
2
1 18- 1 19j0.5
n v = 1.4872
X' to X4 = CH,
1
0
__
~~~* * * 0"
0'
0
0
1 19- I24/0.3
nL5 = 1.4573
XI to
0
~-~~
167- 172/3.0
XS = X6 = CH,; X1 to X4 =- H
**
N-butylmor.
pholine) exhibit good fungicidal action, especially
when the hydrocarbon chain attached to the nitrogeri
339
-
Taable4. The effect of quaternization on the fungicidal action and on the phytotoxicity of tetrahydroI ,4-oxazines [*I
Infection of the leaves after spraying with
an x % solution of the compound
Compound
x = 0.2
0.025
'0
0.00 I5
0.006
0
1
0
R = CH3; Y = 03SOCH3
0
0
0
__
0
-
0
0
0
'0
'
0
0
0
1
2
3
0
0
0
3
0
0
0
1
0
0
0
0
ACH3
*HCOOH
i-CIIHn-NqO
0
1
0
~
CH3
.**
R
3
CH,; Y = O,SOCH,
N-CyclohexyI-2,6-dimethyimorpholine
adipate
N-CycIohexyl-2,6-dimethylmorpholine
benzoate
[ * ] These compounds were obtained in solution only
Table 5. The fungicidal action of tridecylarnine derivatives.
B. p.
Infection of the leaves after spraying
with an x % solution of the compound
Compound
1 x = 0.2 0.1
-
1"C/mml
n
i - C ~ J -HN v~O
16011.5
.I*
0.025 J 0.006
0.001s
~
4
*I*
... -
133-138/1.6
ni5 = 1.4631
D**
-
***
129--133/2.0
uis = 1.4595
3
i- C13Hn - N
~ - C I ~ H ~ - - N R ~ R1=
RZ; H;
R2 s Cyclohexyl
R1 s H ; R2 = Cyclohexyl ;
HOOC-COOH-adduct
***
1 17- 12010.5
n$s = 1.4608
7i
157-167/0.5
l
oil
~~
o
0
0.
oil
'0
R1 = CH,; R2 = Cyclohexyl
152- 156/0.3
***
oil
'
0
_
-_
~
_
oil
R2 s Cyclooctyl
nL5 = 1,4808
340
0
_
O*
0
--
0
"
- -* * * o*
-
114-129/0.5
R1= CH(CH3)-COOH;
I**
0'
RI = H ; R2 = Cyclohexyl;
I /2 Ni(CHsC02)-adduct
R l = CH2-C(CHd-OH
R2 = CH(CH+COOH
'.0
0.
O*
O
1
io
2
-
3
~
1
Angew. Cliem. internat. Edit. / Vol. 4 (1965) 1 N
contains 12 to 18 carbon atoms. With alicyclic N-substituents, the fungicidal properties are considerable even
when the alicyclic group contains only 7-8 carbon
atoms. Alkylated cyclohexyl groups or bicyclic substituents usually d o not lead to the same activity as larger
ring systems (e.g. the cyclododecyl group). Tetrahydroi ,Coxazines with aromatic N-substituents generally d o
not exhibit good fungicidal properties. Howtver, when
the aromatic group is linked to the nitrogen atom by an
aliphatic residue, the fungicidal action will be strongly
increased, particularly if thearomatic group is further substituted with a fairly large aliphatic residue (cf. Table 2).
Table 3 shows that the fungicidal activity of tetrahydro1,4-oxazines is enhanced (relative to unsubstituted or
aromatically substituted compounds of the same type)
by lower alkyl substituents on the C-atoms. Particularly
good fungicidal properties, coupled with low phytotoxicity, are observed when the carbon atoms in positions 2
and 6 of the tetrahydro-l,4-oxazine ring carry hydrogen
atoms and lower alkyl groups. The fungicidal activity
changes only slightly when the free electron pair on the
nitrogen atom of the morpholine ring is blocked (see
Table 4). However, the anion of the resulting quaternary
salt may exert a greater influence.
It can also be seen from Tables 1-4 that compounds
containing alicyclic N-substituents generally have a
lower phytotoxicity than derivatives of comparable or
somewhat better fungicidal action which carry an openchain aliphatic substituent. This applies in particular to
the N-tridecyltetrahydro-1,4-oxazines. The tridecyl
group clearly is exceptional among aliphatic substituents, since many tridecylamine derivatives are good
fungicides; in this respect it is of minor importance
whether the nitrogen atom is further substituted. This
is shown in Table 5 which lists ring systems differing
from tetrahydro- 1,4-oxazine.
In conclusion it can be said that substitution of the nitrogen in tetrahydro- l ,4-oxazine by an alicyclic group
containing more than 7-8 carbon atoms frequently results in good fungicidal properties. A further increase in
the fungicidal activity is caused by aliphatic or alicyclic
N-substituents containing 12-18 carbons, and by one or
two lower alkyl substituents, preferably in positions 2
and 6 of the tetrahydro- 1,4-0xazine ring.
Received: November 27th, 1964
[A435/211 IE]
German version: Angew. Chern. 77, 327 (1965)
Translated by Express Translation Service, London
The Function of the Promotors in the Technical Ammonia Catalyst
BY DR. R. KRABETZ AND DR. CL. PETERS
BADISCHE ANILIN- & SODA-FABRIK AG., LUDWIGSHAFEN/RHEIN (GERMANY)
Published on the occasion of the 100th anniversary of' the establishment of Badixhe Anilin& Soda-Fabrik AG., on April 6th, 196.5.
An attempt is made to give a phenomenological description of the relationships between
the catalytic activity and the distribution of the promotors in the reduced ammonia catalyst.
Investigations were carried out on series of catalysts whose compositions were gradually
brought closer to that of technical ammonia catalysts by the addition to iron of one new
activator (A1203,K 2 0 , CaO, MgO, Si02) at a time.
Following the elucidation of the composition of a catalyst suitable for the technical synthesis of ammonia by
Mittasch [l], numerous investigations were carried out
on the function of the activators. Publications on this
topic up to 1955 are reviewed in monographs by
Frankenburg [2], Bokhoven, van Heerden, Westrik, and
Zwietering 131, and Nielsen [4]. More recent papers have
[ I ] A . Mittasch: Geschichte der Ammoniaksynthese. Veriag
Chemie, Weinheim/Bergstr. 195 I .
[21 W . G. Frankenburg in P. H. Emmett: Catalysis. Reinhold
Publishing Corp., New York 1955, Voi. HI.
131 C. Bokhoven, C. van Heerden, R . Wesfrik,and P . Zwietering in
P . H. Emmett: Catalysis, Reinhold Publishing Corp., New York
1955, Vol. 111.
[41 A . Nielsen: An Investigation on Promoted Iron Catalyts for
the Synthesis of Ammonia. 2nd Edit., Jul. Gjellerups, Copenhagen 1956.
Anpcw. Cliem. intermit. Edit. I Val. 4 (1965) / Nu. 4
dealt with the kinetics of the reaction over singly and
multiply promoted catalysts [5-7d], the mechanism of
reversible poisoning 181, and the reaction kinetics in the
[S] A . Ozaki, H . Taylor, and M . Boudarr, Proc. Roy. SOC.(London) Ser. A. 258, 47 (1960).
[61 R. Krabetz and Cl. Peters, Ber. Bunsenges. physik. Chem. 67,
381 (1963).
[71 R. Brill and S. Tausrer, J. chem. Physics 36, 2100 (1962).
[7a] H . Kubota and M . Shindo, Chem. Engng. (Japan) 23, 242
( I 959).
[7b] J . Scholten, Thesis, Delft 1959.
[7cl K.Tamaru: Actes 2. CongrPs International de Catalyse
Technip, Paris 1961, Vol. I, p. 325.
[7dl S. Enomoto and J. Horiuti, J. Res. Inst. Catalysis Hokkaido
Univ. 2, 87 (1953).
[8] A . V . Krylova and E. Ch. Jenikejew, Chem. Techn. 15, 231
(1963).
34 1
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