Note: Descriptions are shown in the official language in which they were submitted.
7~967
This applica-tion is a division of application No.
498,662 filed on December 27, 1985.
The present invention rela-tes to a process for
preparing substituted furans.
Furans with up to four substituents and the
general formula (I)
R2 ~R3
~l~o~Rb (I)
in which R1 to R4 are each hydrogen or unsubstituted or
halogen-, haloalkyl-, alkoxy-, haloalkoxy-, nitro-, cyano-,
dialkylphosphonyl- or alkoxycarbonyl-subs-tituted alkyl,
aryl, aralkyl, al]~oxycarbonyl or dialkoxyphosphonyl, R3 is
also hydroxyalkyl which is unblocked or blocked by a
detachable protective group, are needed as precursors, for
example for preparing crop protection agents. It is known
that furans can be prepared from 1,4-dilcetones by
cyclization (Comprehensive Heterocyclic Chemistry 4 (1984)
657 et seq. In the synthesis o:E in par-ticular
asymmetrically substituted furans (for example 2,4-
disubstitution), the preparation of the starting materials
reg;uired is difficult. For that reason, various methods are
recommended for preparing for example 3-benzyl-4-hydroxy-
methylfuran, a desirable intermediate for insecticide
syntheses (JCS (c) 1971, 2551; Wegler 7 (1981) 76; German
Laid-Open Application DOS 2,122,823). However, all these
methods have serious disadvantages (multistage syntheses
with moderate overall yield; safety problems due to high
temperatures; formation of isomers).
The object of the present invention is to provide
a new process for preparing substituted furans, which uses
.~$
~7~
- la -
readily available starting materials and is easy to carry
ou-t.
I-t has now been found tha-t this object is achieved
by a process wherein furans of the above men-tioned kind are
obtained advantageously by hydrogenating a corresponding
isoxazoline of the formula II
~R2
ll ~R~ (II)
N~ ~ ~ R'~
X
in which:
R , R , R3 and R4 are each hydrogen or unsubstituted or
halogen-, haloalkyl-, alkoxy-, haloalkoxy-, nitro-, cyano-,
dialkylphosphonyl- or alkoxycarbonyl-substituted alkyl,
aryl, aral]cyl, alkoxycarbonyl or dialkoxyphosphonyl, R3 is
also hydroxyal]cyl which is unbloc]ced or blocked by a
detachable protective group
~,
.' .
~7~6~
- 2 - O.Z. 005~/37514/37691
and X ;s hydroxyl, halogen or hydroxyl wh;ch ;s
blocked by a detachable protective group.
The hydrogenation of subst;tuted ;soxazol;nes ;s
known in princ;ple tJ. Am. Chem. Soc. 104 (1982), 40Z4;
Tetrahedron Lett. _ (1982~, 3123 and 2~ (1983), 1337~
and has also been used for the synthes;s of heterocycles.
For ;nstance, su;tably subst;tuted isoxazolines can be
made to undergo hydrogenating cleavage to give pyrones
(US Patent b,136,114), pyridines (J. Org. Chem. 36 (1971),
1Q Z784~, pyr;midines and pyrimidones ~J. Pharm. Soc. Jap.
83 ~1963), 471 or Ann. ChimO 60 ~1970), 393), pyrroles
(Ann. Chim. 56 (1966), 85S)~ pyrazoles (Chem. ~er. 106
(1973), 332 or Tetrahedron~ _ (1973), 4291), im;dazoles
(Ann. Chim. 60 (1970), 343) or even furanones (Tetrahe-
dron Lett. (1983) 2079 or (1966) 233 or (1967) 327 orGa~etta ( 196b) 1073).
The Formation of the furans according to the in-
vention is not observed in any of these hydrogenations,
although suitably substituted starting materials (ie. 5-
Z0 hydroxymethyl-substituted isoxazolines - eg. J. Am. Chem.
Soc. 105 (1983), 5~26-5833); co~mpound 18 a) have been
used in this reaction. Only Acta Chem. Scand. ~ 36 (1982),
1-14 describes an acid-catalyzed rearrangement of isoxa-
zolines under nonhydrogenating conditions where a speci-
fic substitution produced a furan der;vat;ve v;a a dike-
tone intermediate. Slightly d;fferent substitut;on pat-
terns produced not furan derivat;ves but furanones and
cyclopentenones.
Isoxazol;nes of the general formula II, except
those in wh;ch R1 or R3 ;s hydrogen, are novel substances.
It w;ll be read;ly understood that in those cases where
R is etherif;ed or ester;f;ed hydroxymethyl and at the
same time X ;s blocked hydroxyl an ether;f;cation or es-
terification may have taken place with a bifunctional re-
actant together with cyclization. Depending on the spe-
cific method, this- result can be o~btained directly or it
is possible to isolate the hydroxyketone III
.
- 3 - O Z. 0050/37514/37691
Ql ~ R2 (III)
ll ,~R3
o ~ ~R4
OH
as an ;ntermediate and to obtain the desired furan
derivative in 3 subsequent step:
R 4 ~ R ~ RR 3
(II) (III) (I)
In the case of the abovementioned 2-benzyl-
4-hydroxymethylfuran the reaction can be represented as
follows:
OH H2/cat ~OH
N~ R O H I H~3 ~
The smooth course of this reaction is, inter alia,
also surprising because hitherto the hydrogenation of
specifically substituted isoxazoles has merely been des-
cribed as a method of synthes;zing the hydrofuran-3-ones
(Tetrahedron Lett. (1983) 2079 Tetrahedron Lett. ~1966)
233; Tetrahedron Lett. (1967) 327; Gazetta (1966) 1073):
,~o
H2/ Cat ,~ J<
N~O~O H - ~ O
Furthermore, a spec;fic isoxa~oline substitution in
the reduction with TiCl3 produced 2,5-disubstituted furans
(Acta Chem. Scand. L 36 (1982):
COOR
rl ~
N~O~ ~O COO~le
o
~ ;~7~ 7
- 4 - o.Z. 0050/37514t37691
The novel precursors II are prepared in particu-
lar as follows:
Isoxazolines II
Rl Q2
~R3
N~ ,~R" ( I I )
can be obtained for example by the method in Heterocycles
1Z (1979), 1Z43 et seq. by reacting nitrile oxides with
certa;n olefins as shown by
x
r O - - - ~ R 2~R ~
~ (II)
R3
R 2~R ~
In the preceding reaction, X is hydroxyl which is
unblocked or blocked by a detachable protective group,
for example t-butyl, trimethylsilyl, acetyl or benzyl.
Incidentally, some of the isoxazolines according to the
invent;on can be obtained from other isoxazolines wh;ch
are obtainable by the preceding method; for example, at
the hydroxyl groups of 5,5-b;s-hydroxymethyl;soxazol;ne
which is substituted in the 3-position it is possible to
introduce or detach the abovementioned protective groups
or for example hydroxyl and halogen or halogen and a pro-
tective group can be exchanged for each other.
The n;tr;le ox;des requ;red as start;ng mater;als
can in turn be obta;ned from for example correspond;ng
oximes or from al;phat;c n;tro compounds~
In th;s context, reference ;s made to Hetero-
cycles, loc. cit. and the references cited there;n and to
Z5 Houben-Weyl, Methoden, 14th ed;t;on volume 10/3 page 83
and to J. Org. Chem. 28 (1~63), 1150~ Spec;fic aspects
of the asymmetr;cal induction in this ;soxazol;ne synthe-
sis have been dealt ~;~h by Jager and Schohe (Tetrahedron
7~
- 5 - O.Z. 0050/37514/37691
Lett. Z4 (1983), 5301-04).
The isoLation of the nitrile oxides of the for-
mula II is not absolutely necessary. They are
advantageously produced straight away in the presence of
the alkenyl compounds with which they react immediately
to give the isoxazolines of the formula II.
The nitrile oxides used for preparing the ;sox-
azolines and the alkenyl compounds can be used in
equ;molar ratios or can each be used in excess over the
other reactant.
Suitable solvents for the react;on are for
exar~ple the spec;fic alkenyl compound itself, aromatic
compounds (for example benzene, toluene or xylene),
halogenated aromatic compounds, ketones (for example
acetone, methyl ethyl ketone or diisopropyl ketone),
ethers (for example dioxane, diethyl ether or THF) or
chlorinated aliphat;c hydrocarbons (for example dichloro-
ethane, chloroform or methylene chloride).
It is noteworthy that the course of the addition
of the olefins onto these nitrile oxides depends on the
nature of the substituents and therefore that in certain
circumstances isomers or mixtures of isomers are likely.
A likely general rule is that the side of the olefinic
bond ~hich is added onto the oxygen atom of the nitrile
oxide is that side which carries the bulkier substituent.
All the reactions described above usually pro-
ceed at an adequate rate below about 150C.
A further way of obtaining ;soxazolines is
revealed by Preparative Example Z below.
....
;,.,,. ;. -
,
~'7~6~
--6--
PR~PARATIVE EXAMPLE 1 FOR AN ISOXAZOLINE
O-C-CH3
O-C-CH3
159 g of phenylacetaldoxime and 202.5 g of
isobutylene diacetate are dissolved in 500 ml of diethyl
ether, and 1050 ml of a 10% strength sodium hypochlorite
solution are added to the vigorously stirred solution at
from 10 to 15C. Stirring is continued for several hours,
after which the organic phase is extracted by shaking with
water, dried over sodium sulfate and freed from the
solvent.
The yield is 333 g ( _ 92.8% of theory).
Crystals obtained by crystallization from ethanol/petroleum
ether melt at 78 - 79C.
PREPARATIVE EXAMPLE 2 FOR AN ISOXAZOLINE
1960 g of 10% strength NaOH solution are added a
little at a time to 200 g of allyl acetate and 242 g of 2-
methylbutyraldoxime in 600 g of methylene chloride, and the
mixture is stirred for 3 hours at room temperature. The
organic phase is separated off, washed with water, dried
over Na2SO4 and filtered, and the filtrate is freed from
the solvent. The oil which remains (339 g) is 3-sec.-
butyl-5-acetoxymethylisoxazole.
300-MHz-NMR spectrum in CDCl3 (ppm): 0.95 (3H);
1.08 (3H); 1.2-1.3 (2H); 2.04 (3H); 2.3 (lH); 2.35 (lH);
3.0 (lH); 4.0-4.1 (2H); 4.4 (lH).
PREPARATIVE EXAMPLE 1 FOR A FURAN
88.4 g of 3-benzyl-5,5-bis-(hydroxymethyl)-
isoxazoline are taken up in 550 ml of tetrahydrofuran, 40
ml of water and 80 ml of glacial acetic acid, and 1.6 g of
'~
~ ';
~7~
platinum oxide are added. When hydrogen is passed in, a
slightly exothermic reaction takes place. When absorption
of hydrogen is complete, the mixture is filtered, the
filtrate is evaporated down and the residue is stirred with
acetone. The undissolved ammonium acetate is filtered
off, the filtrate is evaporated down again, and the residue
in 300 ml of methylene chloride is then stirred with 300 ml
of 10 % strength hydrochloric acid for 1 hour at 20C.
Thereafter, the solution in methylene chloride is separated
off, washed with water and evaporated down to give 59.2 g
(79%, based on isoxazoline) of 2-benzyl-4-
hydroxymethylfuran, which is virtually pure according to
NMR spectroscopy. Distillation (125-128/0.3mm) gives 52.0
g of a substance having a melting point of 37 - 38C.
PREPARATIVE EXAMPLE 2 FOR A FURAN
100 g oE 3-sec.-butyl-5-acetoxymethylisoxazole
in 400 g of methanol and 27 g of water are hydrogenated at
20 - 30 using 25 g of Raney nickel. Thereafter, the
mixture is filtered and the filtrate is freed from the
solvent and distilled. The liquid which distils over a-t
70 - 80 C is 2-sec.-butylfuran. 200 MHz-NMR spectrum in
CDC13 (ppm): 0.9 (3H); 1.25 (2H); 1.5-1.8 (2H); 2.78 (lH);
6.0 (lH); 6.3 (lH); 7.35 (iH).
Other isoxazolines can be prepared from
appropriate starting materials, using the above methods.
For example, the substances listed in the Table below have
been prepared, these substances giving an idea of the
versatility of the novel process and of the active
ingredients and their intermediates which are obtainable by
means of this process.
~ ~7~6
-- 8 --
O.Z~ 0~50/37514~3~691
Rl R2 R3 R~ X
- e Kp ~13i-136U:
CH3 HCH3--C-0CH2 HCH3-C-O M :1,$572
- - O o 00 MHz--NMR in COC13lPP~I:
~ U 1,~13H); 2,1s~6H) 3,2l2H);
C2tls-OOC HCH3-C-OCHz HCH3-C-O ~,2-~,616H1:
.
HCH3-C-OCH2 HCH3-C-O Fp = 79-80C
CH2 HCR3-C-OCH2 HCH3-C-O Fp = 7a-79c
.
~ CH2 H CH2-OH H OH Fp = 6a-7~Dc
O
CH3-OCH2 H CH3 CH3-C-O p0 2=107-11 oD C ~
- ~
Cl O 200 MHz-NMR ln COC13 IPPm~
¦¦ ~ 2,06(6H)- z,al2H~; 3,B112H1
Cl ~ ~-CHz HCil3-C-OCH2 HCH3-C-O ~,16l~HI, 7,25(2H)
-
F ~ CH2 H Cil2OH H OH Fp = 93-97C
-
CF3 O O 300-MHz-NMR in COC13 Ippml
2,0116Ht- 2,~12H~;
CH2 HCH3-C-OC"2 "CH3-C-O 3,75~2H), ~,0~-~,2316H);
CH3 O O 300-MHz-NMR in SOC13 IPpml
1,53(3H~; 2,0(3H);
C~ HCH3-C-OC'12 "CH3-C-O 2,03(3H); 2,71(2H);
'=' 3 02(1H); ~,1212H);
~ 1$l2H).
