CA1331383C - Preparation of heterocyclic aromatic aldehydes and ketones - Google Patents
Preparation of heterocyclic aromatic aldehydes and ketonesInfo
- Publication number
- CA1331383C CA1331383C CA000583240A CA583240A CA1331383C CA 1331383 C CA1331383 C CA 1331383C CA 000583240 A CA000583240 A CA 000583240A CA 583240 A CA583240 A CA 583240A CA 1331383 C CA1331383 C CA 1331383C
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- membered
- carbon atoms
- hydroxymethyl
- organic
- ketones
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
- C07D213/46—Oxygen atoms
- C07D213/48—Aldehydo radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
- C07D213/46—Oxygen atoms
- C07D213/50—Ketonic radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
?9 Abstract of the Disclosure A process for the preparation of heterocyclic aromatic (heteroaromatic) aldehydes and ketones of the general formula (I), (I) where Arhet is a five-membered or six-membered heteroaro-matic radical having at least one nitrogen atom and R' is hydrogen or an alkyl radical of from 1 to 20 carbon atoms, by oxidation of the corresponding 1-hydroxyalkyl compounds (II) (II) wherein the oxidant is an inorganic or organic hypochlorite or hypobromite (III) in conjunction with an alpha,alpha,omega,omega-tetraalkylcycloalkane of the general formula (IV), (IV) where the radicals Alk are identical or different alkyls of from 1 to 4 carbon atoms, Q is one of the groups >N+=O X- ; >N-OH or >N-O
(X- is an anion), n is either 0 or 1, and Y is oxygen, carbonyl, or >CR2R3; R2 and R3 are hydrogen, hydroxyl, or organic radicals in which the free valency is attached to carbon or oxygen and that may be linked to form a five-membered or six-membered ring.
(X- is an anion), n is either 0 or 1, and Y is oxygen, carbonyl, or >CR2R3; R2 and R3 are hydrogen, hydroxyl, or organic radicals in which the free valency is attached to carbon or oxygen and that may be linked to form a five-membered or six-membered ring.
Description
oz io50jj~587 Preparation of heterocyclic aromatic aldehydes and ketones The present invention relates to a novel process for the preparation of heterocyclic aromatic ~heteroaromatic) aldehydes and ketones of the general formula (I), O
Arhet~ll~Rl where Ar~t is a five-membered or six-membered heteroaro-matic radical having at least one nitrogen atom and R1 is hydrogen or an alkyl radical of from 1 to 20 carbon atoms, by oxidation of the corresponding 1-hydroxyalkyl compounds (II).
,, : Arhet~CH~
.
-~ 15 It is well known that aldehydes and ketones can be : prepared by oxidation of the corresponding primary or -~ secondary alcohols~
OH o R--CH--R Ox. R--C--R
The oxidation of al~phatic alcohols is usua,lly re~lativel,y easy, and many isoaromatic alcohols, for instance benzyl alcohol, are converted to the aldehydes simply by the ac--~ tion of atmospheric oxygen. The preparation of heteroaro-matic aldehydes from the appropriate hydroxymethyl com-:~ pounds presents some difficulties however; for example, to obtain pyridinecarbaldehydes, oxidants such as sele-- nium dioxide, lead tetraacetate, or manganese dioxide ~ 3 3 ~
~Z ~5G/3?'~?
~ .
have been used -- cf. Ullmanns Encyclop~die der technis-chen Chemie, 3rd ed., vol. 14, p. 478 (1963). Much the same can be said of heteroaryl alkyl ketones. For exam-ple, oxidation of the appropriate alcohols with chromium trioxide and sulfuric acid or with manganese dioxide has been used for the preparation of the particularly impor-tant pyridyl alkyl ketones -- cf. Deljac et al., Acta Pharm. Jugosl., 32(4), 267-74, Chem. Abstr., 98, 174241t, and ~S-A 4 098 908. Apart from the fact that the use of these expensive and physiologically somewhat dubious oxidants that have to be employed in solid form presents considerable technical difficulties, the yields and selectivities attained are mostly unsatisfactory.
It is known from the work of Anelli et al. -- J. Org.
Chem., 52, 2559-62 (1987) -- that some aliphatic and iso-aromatic alcohols can be successfully oxidized to the corresponding carbonyl compounds by sodium hypochlorite in the presence of potassium bromide and catalytic amounts of the piperidine derivatives R R R
O X~ 1H O
R = H; CH 3 X = Cl; ~r However, these workers make no mention of investigations relating to heteroaromatic hydroxymethyl compounds or heteroaromatic aldehydes and ketones.
The aim of the present invention was to make certain heteroaromatic aldehydes and ketones accessible in a sim-pler and more economic manner than hitherto. Accordingly we have found a process for the preparation of hetero-cyclic aromatic (heteroaromatic) aldehydes and ketones,ofthe general formula ~I), O
Arhet-C-R
(I) 3 13 313 8 3 ~z 0050j395~?
where Ar~t is a five-membered or six-membered heteroaro- :
matic radical having at least one nitrogen ato~ and R1 is hydrogen or an alkyl radical of from 1 to 20 carbon atoms, by oxidation of the corresponding 1-hydroxyalkyl compounds (II) IH ~:
Arhet-C~R
(II) wherein the oxidant is an inorganic or organic : hypochlorite or hypobromite (III) in conjunction with an ~
alpha,alpha,omega,omega-tetraalkylcycloalkane of the ~ :
general formula (IV), ~ ;~
(Y) , , ~ :-A I k~ A I k ( IV) : : where the radicals Alk are identical or different alkyls ~ 15 of from 1 to 4 carbon atoms, Q i5 one of the groups , ~
>N'=O X~ ; >N-OH or >N-O-(X- is an anion), n is either 0 or 1, and Y is oxygen, carbonyl, or >CR2R3; R2 and R3 are hydrogen, hydroxyl, or ~- organic radicals in which the free valency is attached to carbon or oxygen and that may be linked to form a five-~ . membered or six-membered,ring.
- We have also found that the reaction proceeds particu-larly successfully if it is carried out in the presence ~:: c of catalytic amounts of an inorganic bromide, if -- inde- :
pendent of the use of bromide -- it is carried out in a '~ two-phase system of water and an organic solvent, and if ::
- the pH is kept between 5 and 10. :~
;: , ,~ ~
1! ~ 3 ~ 3 8 3 oz ~OSC~3~7 The radical Ar~c in the product of the process (I) or :
the starting compound (II) corresponds to one of the fol~
lowing heteroaromatic systems (R4 is an alkyl of from 1 ~:
to 4 carbon atoms or benzyl):
~ ::
l4 pyrro e 1~3 ;'' R4 pyrazole ~l~ imidazole isoxazole oxazole ~:
1~
:: N`N-N
~; 15 14 1,2,3-triazole ~ :
~_N
N`~ 1, 2,4-triazole . R4 ~,~ 20 N~ 1, 2,3-oxadiazole ~N 1 ,2,4-oxadiazole ! ' j j j 1,2,5 oxadiazole N~N
N_N
~ 1,3,4-oxadiazole ~ ~ pyridine ,........................................................................ ..
' ~ ~
',.
..
~.
1 3 3 1 3 8 3 I7~~1~J5lJ,/'3587 ~ pyridazine N~
~NJ pyrimidine ¢~ ;
pyrazine In the starting compound (II) the 1-hydroxyalkyl group can be attached to any ring carbon atom. The remaining carbon atoms can carry any organic radical that is inert -- that is to say, non-oxidizable -- and in which prefer-ably a carbon atom has the free valency; examples of suchradicals are - alkyls of from 1 to 8 carbon atoms, such as methyl, ethyl, and isopropyl; ~ ~`
- cycloalkyls of from 3 to 12 ring carbon atoms, such~ ~
as cyclopentyl and cyclohexyl; ;~;
~ ~ .
- five-membered and six-membered oxacycloalkyls, such as 2-, 3-, and 4-oxacyclohexyl and 2- and 3-oxacyclopentyl;
- cycloalkylalkyls, such as 1-cyclohexylethyl and 2-cyclohexylethyl;
- aryls, such as phenyl, 1-naphthyl, and 2-naphthyl;
- arylalkyls, such as benzyl, 1-phenylethy}, and 2--~ phenylethyl;
- acyls R'-CO-, where R' is one of the radicals given above, such as acetyl and benzoyl;
- organyloxy radicals R'-O-, where R' is one of the alkyls, cycloalkyls, oxacycloalkyls, cycloalkyl-alkyls, aryls, or arylalkyls given above;
- oxycarbonyl radicals R'-O-CO-, such as methoxy-carbonyl and phenoxycarbonyl;
.~ -:
~ - carbonyloxy radicals R'-CO-O-, where R' is one of -~ the radicals defined above.
It is also possible for the oxazole, isoxazole, 1,2,3-- 35oxazole, 1,2,5-oxazole, and pyridine systems to form part '. '~
::
6 13 3 ~ 3 8 3 oz oGso/3ssa7 of fused systems, as in benzoxazole, benzisoxazole, and quinoline. The inert radicals named above can be them-selves substituted by fluoro, chloro, bromo, or cyano radicals, or by alkoxy radicals of from 1 to 4 carbon atoms. -The radical R1 can be hydrogen or an alkyl of from 1 to 20 carbon atoms.
The starting compounds (IIJ are known or can be ob- ~-tained by known methods. The hydroxymethylisoxazoles (IIa)-(IIc), which are particularly important because of the products they yield, can for instance be prepared as follows (R3 and R~ are organic radicals):
''-.
Me~CO~a~ H2NOHNaBH4 HO-CH2~3~R3 (lIa) -- cf. J. Org. Chem., 26, 1514 (1961) --,.
; R~ ~ o~e HzNOH LiAIH~ ~4 ~ CH2-CH
;~ (IIb) . ,:~
~ -- cf. ~er., 42, 3912 (1903) --, ::~
'- ~' , R3~ H R3 ~ CH2OH
(IIc) ~ -~
-- cf. DE-A 27 54 832 -~
- Something similar applies to the other starting compounds - (II).
The following are important starting compounds (II) -`
for the preparation of intermediates (I) that are used -~
for the synthesis of known crop protection agents (cf.
DE-A 36 09 181, for instance)~
,,. ~';,;
: ~ .
7 i33~ 383 1~ 050/3~58?
5-(hydroxymethyl)-3-methyIisoxazole --5-(hydroxymethyl)-3-ethylisoxazole 5-(hydroxymethyl)-3-propylisoxazole 5-(hydroxymethyl)-3-isopropylisoxazole :
5-(hydroxymethyl)-3-butylisoxazole 5-(hydroxymethyl)-3-isobutylisoxazole 5-(hydroxymethyl)-3-(sec-butyl)isoxazole 5-(hydroxymethyl)-3-(tert-butyl)isoxazole S-(hydroxymethyl)-3-(ethoxycarbonyl)isoxazole 5-(hydroxymethyl)-3-cyclopropylisoxazole 5-(hydroxymethyl)-3-cyclobutylisoxazole 5-(hydroxymethyl)-3-cyclopentylisoxazole ~.
5-(hydroxymethyl)-3-cyclohexylisoxazole 5-(hydroxymethyl)-3-(2-oxacyclohexyl)isoxazole 5-(hydroxymethyl)-3-(3-oxacyclohexyl)isoxazole :-5-(hydroxymethyl)-3-(4-oxacyclohexyl)isoxazole ~`
: 5-(hydroxymethyl)-3-(2-oxacyclopentyl)isoxazole 5-(hydroxymethyl)-3-(3-oxacyclopentyl)isoxazole 4-(hydroxymethyl)-3,5-dimethylisoxazole 3-(hydroxymethyl)-5-isopropylisoxazole ~:
5-(1-hydroxypentyl)-3-methylisoxazole ~` 5-(1-hydroxyhexyl)-3-(ethoxycarbonyl)isoxazole ::
1-benzyl-2-(:1-hydroxyhexyl)imidazole :
3-(hydroxymethyl)pyridine 2-(hydroxymethyl)pyridine ~~. 4-(hydroxymethyl)pyridine ~-~- 3-(1-hydroxyhexyl)pyridine :~
:~: 3-(2-ethyl-1-hydroxypentyl)pyridine ~:
~- 3-(1-hydroxypentyl)pyridine ~::
The oxldant is~an inorganic or organic hypochlorite or hypobromite tIII), referred to subsequently as the hypo-halite. Suitable inorganic hypohalites include sodium ~- hypochlorite in particular, but also potassium hypochlo- -~:~
;~ ~rite,, calcium hypochl,orite~ and sodium hypobromite; they : 35 are preferably employed as aqueous solutions, in which :
-~ the mass fraction of hypohalite is from about 5% to 20%, ~:~
''~- prepared from :the pure salts or by treating solutions of . ~ the alkali or alkaline-earth hydroxides with chlorine or ~-~: bromine. The most suitable organic hypochlorites and hy-pobromites are tertiary hypohalites, of which tert-butyl : .
hypochlorite is predominant.
,,, .
.:, , 3 1331 3830~ JC5u/J~C~' For complete oxidation of an alcohol (II) to a car-bonyl compound (I) it is necessar~ to use at least equimolar amounts of the hypohalite (III); generally it is recommended that the mole ratio of the excess amount of hypohalite (III) to the initial amount of alcohol should 'De Up to 50~. If either the alcohol (II) or the carbonyl compound (I) is very sensitive to oxidation it can be advisable to limit conversion by starting with less than the stoichiometric amount of hypohalite ~III), -equivalent to a mole ratio of roughly from 50% to 90 based on the initial amount of alcohol (II).
An essential feature of the novel oxidation process is the use of compounds of the general formula (IV), which function as catalytic oxygen transfer agents. These com-pounds are primarily the piperidine derivatives lIVa)~(IVc), Alk ~ ~ Alk Alk ~ ~ AlkAlk ~ ~ Alk Alk 11 Alk Alk I Alk Alk ~ Alk O Xe OH ~.
; IVa IVb IVc - of which the 2,2,6,6-tetramethyl derivatives are most im-portant because they are the most easily accessible. The nature of the group Y has only a secondary influence on the course of the reaction, and in principle almost any group is possible; however, for economic reasons the com-pounds (IV) are preferably simple ones in which the group ~ ;
Y is oxygen, carbonyl, methylene, 1,1-ethylene, hy-droxymethylene, or methoxymethylene.
The anion X~ can be almost any anion in principle, but for practical reasons sulfate, p-toluenesulfonate, ac-etate, and, above all, chloride and bromide are preferred. ~ i ' ! i` `
The piperidine derivatives (IVa)-(IVc) can be obtained by known methods -- cf. Synthesis, 191 (1971), for in-stance -- and are stable. They can be used as they are, but when together with a hypohalite (III) and the alcohol (II) that is to be oxidized they are interconverted in the course of the catalytic oxidation cycle; presumably the oxide ~IVa) is the immediate oxidizing agent. ;~
133~ 383 The piperidine d~rivatives (IVa)-(IVc~ can be empioyod direct or formed in situ by treating the appropriate piperidine compounds with an oxidizing agent. Suitable oxidizing agents are above all peroxides, such as hydro-5gen peroxide -- preferably accompanied by sodium tungstate or a similar compound of the o~ide of a metal in a high oxidation state --, especially organic perox-ides, such as m-chloroperbenzoic acid.
The remarks about the piperidine derivatives lIVa)-lO(IVc) apply analogously to the corresponding pyrrolidine compounds, so there is no need to discuss these separately.
The amount of compound (IV) used is optional in prin-ciple, but since catalytic action is required the mole 15ratio of the amount of compound (IV) to the initial amount of alcohol tII) is preferably from 0,1~ to 20~. If the ratio is less than 0.1~ the reaction proceeds too slowly, and a ratio greater than 20~ offers no worthwhile advantage.
20Since water is formed in the reaction, and the hypo-halite (III) is preferably employed in aqueous solution, there is always an aqueous phase. It is however advisable to provide an organic phase in which the organophilic re-;~ actants can dissolve and which will take up aldehydes (I) 25in particular and protect them to a certain extent from subsequent reactions; this is done by also using a solvent that is immiscible with water, such as methylene chloride, chloroform, ethyl acetate, butyl acetate, diethyl ether, or toluene. The quantity of this ~ 30immiscible solvent is not critical: generally it is from ;~ 1 kg to 10 kg per kilogram of alcohol (II).
It is also advantageous to adjust the pH of the aque-ous phase to a value between 5 and 10 and to keep this ~; value constant by means of a buffer such as sodium hydro-35gen carbonate, sodium acetate, or disodium hydrogen ph!os-phate. In more acid solutions the hypohalites (III) are less stable, and in strongly alkaline solution the alde-hyde lI) that is formed may take part in undesirable re-actions.
40The novel reaction is further promoted by bromide - ions, which are conveniently introduced as sodium or - potassium bromide, the mole ratio relative to the amount ~" ",," ,,,, "., "..,,","s ...",: .,." ,, ,,, ~ "",, ",, ~," ,,,,, -;",, ~ ,", ,"":-~;",: ,"; " ~ ~,", .
~f," . , .. ... ... , .. ,, ,. ,.,. ,, . - , ,,, -: : : . .. : :. :,.,:: ::. : .: :: .:.. -:.. .
lo 1 3 3 ~ 3 8 30z 00SU/~ j587 of alcohol (II) being from 1~ to 10~. No bromide needs to be added if the oxidant is hypobromite, since bromide ions are then formed anyway.
It is recommended that the reaction temperature is from 0 C to 100 C, preferably from 0 C to 40 ~C Gen-erally the process is carried out under atmospheric pres-sure or, if a volatile solvent is used, the vapor pres-sure of the reaction mixture.
It is technically convenient to mix all thé components except the hypohalite (III), so that a two-phase system is formed, then to add hypohalite gradually, say over a period of from 30 min to 10 h. Apart from this, the pro-cess has no technical peculiarities and needs no further description. The same applies to subsequent treatment of the reaction mixture, in the course of which the carbonyl compound (I) that is formed is isolated from the organic phase in the usual way. The aqueous phase left behind, which contains excess oxidant, catalysts, and buffer, can be used for further charges. Any hypohalite that remains in the organic phase can be destroyed by means of a re-ducing agent, such as iron(II) sulfate.
The yields of heteroaromatic aldehydes and ketones (I) are unexpectedly high: up to about 85%. The products are valuable intermediates for, inter alia, crop protection agents.
Example 1 Preparation of 5-formyl-3-(tert-butyl)isoxazole tI/1) Over a period of 3.5 h 1765 g of an aqueous solution con-taining 14~ by weight of sodium hypochlorite (3.3 mol) was added to an intensely stirred mixture of 465 g (3 mol) of 5-(hydroxymethyl)-3-(tert-butyl)isoxazole, 9.4 g (0.06 mol) of 2,2,6,6-tetramethylpiperidin-1-oxyl, 17.9 g (0.15 mol) of potassium !bromide, 46.8 g j(0.3 mol) of sodium dihydrogen phosphate dihydrate, 53.4 g (0.3 mol) of disodium hydrogen phosphate dihydrate, 1800 ml of methylene chloride, and 1800 ml of water at 20 C. During the whole of the reaction time the pH of the reaction mixture remained fairly constant between 6.5 and 7.5.
~.~
I 1 1 3 3 1 3 8 3 z 0050/~5~7 The organic phase was separated off and the aqueous phase extracted with methylene chloride. The combined or-ganic phases were washed with aqueous sodium hydrogen carbonate and treated as usual to isolate the aldehyde (I/1 ) .
Yield: 77~
b.p.: 82-4 C/0.01 mbar ~-m.p.: 42-3 C
Example 2 , ~
Preparation of 5-formyl-3-isopropylisoxazole (I/2) Over a period of 75 min 10.9 g (0.1 mol) of tert-butyl hypochlvrite was added to a stirred mixture of 14.1 g (0.1 mol) of 5-(hydroxymethyl)-3-isopropylisoxazole, 1.6 g (0.01 mol) of 2,2,6,6-tetramethylpiperidin-1-oxyl, 16.5 g (0.1 mol) of sodium dihydrogen phosphate dihydrate, 6Q
ml of methylene chloride, and 60 ml of water at 20 C, and the mixture was stirred for another 30 min. The pH
w~s about 8.
The aqueous phase was extracted with methylene chlo-ride, and the extract was combined with the original or--~ ganic phase, which was then washed successively with 30 -~ ml of dilute hYdrochloric acid, 30 ml of saturated aque-ous iron(II) sulfate solution, and sodium hydrogen car-~ 25 bonate solution. Finally the solution was treated as -~ usual to isolate the aldehyde (I/2).
Yield: 73%
`- b.p.: 74 C/4 mbar - 30 Example 3 Preparation of 5-fo~myl-3-isopropylisoxazole (I/2) A solution of 1.6 g (9.2 mmol) of m-chloroperbenzoic acid ~ in 25 ml of methylene chloride was added dropwise over a -- period of 15 min to a solution of 0.3 g (2.3 mmolj of 2,2,5,5-tetramethylpyrrolidine in- 10 ml of methylene chloride at a temperature of 20 C, and the mixture was stirred for a further 30 min.
':
12 l 3 3 ~ 3 8 3 Z ~050/39587 The catalyst solution prepared in this way was mixed with 40 ml of methylene chloride, 70 ml of water, 0.69 g ~5.8 mmol) of potassium bromide, 16.2 g (0.115 mol) of 5-(hydroxymethyl)-3-isopropylisoxazole, 1.8 g (11.5 mmol) of sodium dihydrogen phosphate dihydrate, and 2.0 g (11.5 mmol) of disodium hydrogen phosphate dihydrate. Over a period of 2 h 67.3 g of an aqueous solution containing 14% by weight of sodium hypochlorite (0.126 mol) was added to the intensely stirred mixture at 25 C, then the mixture was stirred for another 15 min.
The organic phase was separated off and the aqueous phase extracted with methylene chloride. The combined or-ganic phases were washed with aqueous sodium hydrogen carbonate and treated as usual to isolate the aldehyde (I/2)-Yield: 64~
Examples 4-24 Preparation of various aldehydes (I) General procedure (Example 4) To prepare a catalytically active piperidine derivative (IV) a solution of 25.9 g (0.15 mol) of m-chloroperben-zoic acid in 300 ml of methylene chloride was added over a period of 15 min to a solution of 9.3 g (0.06 mol) of 2,2,6,6-tetramethyl-4-piperidone in 150 ml of methylene chloride at a temperature of 20 C, and the mixture was stirred for a further 30 min.
The catalyst solution prepared in this way was mixed with 423 g (3 mol) of 5-(hydroxymethyl)-3-isopropylisoxa-zole, 18 g (0.15 mol) of potassium bromide, 46.8 g (0.3 mol) of sodium dihydrogen phosphate dihydrate, 53.4 g (0.3 mol) of disodium hydrogen phosphate dihydrate, 1350 ml of methylene chloride, and 1800 ml of water. Over a period of 4 h 1756 g of an aqueous solution containing 14~ by weight of sodium hypochlorite (3.3 mol) was added to the intensely stirred mixture at 25 C.
13 1 3 3 ~ 3 8 3 oz 005oi33s87 The same procedure was used in Examples 5-24, the subsequent treatment of the reaction mixture being as de-scribed in Example 1. In each case the pH was from 6.5 to : :
8Ø
5Details of these examples are given in the following table.
'-:
: ' ' ' ~ ~
., ~_ ~ " ~"" ~ " ~"~
;9~:s`~
-- 14 '1 3 3 ~. 3 8 ~ ,,050,39587 o I ~ ~ ~ o,~
h I O O O ~ ~ O ^i h ~: ~ o o I
h ~ 3 0 I td ~ I~ Q. Q, ~ X X ~ ~-- X
~ ~ 0 ~ ~ oa) '`I a~
I q) x Io d O O IQUl tJ T V1 ~: O O
' ~ ~ ' æ c~ ~ ~ æ ~ o ~ æ z : :~
tSI I h I ~ 1 1 o In o ~ I ~ I '::
I ~ I ~ I - - - -I~I IXX XXXX X
~ U , ~ oI ~ I ~ ~1 ~ o I ~ I
u l ~
:~
~:: l o l l ::
I Z H
. I I
I
';'`
~, ~ I I , '' ~ l l ' ~
. . ~ .
o o o o o o o ~, I I X X X X X X X--~ O
O O O O O O OO ~N
~ X O
: I I o~ oP Do. o~ o~ o~ oQ, .0~ ~~ ',:
O O aO oR o~ 04 oQ' L~
. I I I I I I I I I I I
~ H ~ E 6 e ~
H I X ~ X X ~ X X X X
i ~ g '~,::, I ~ I Ln L Ln Ln L~
n Ln Ln Ln Ln . l l .
. I I :
: I , . I :
n ~ o ~ ~ . .
.~
.
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Z C ~
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I
~ l l O
t~ ~ O O ~ O N
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o 1~1 o ~ ~ ~ ~ 1~ In o ~o o ~ r o o I
-:
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I
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Xi ~ X O O
~q o ~ o u~
o ~ o t t~ N - -- -- O
N O ~
O ~-- ~ O ~ ~ ~ X td N
N :~ X In ~ 0 X
X O ~ -- ~ Q, Q. -~ O
O A O ~ O O
- I I -' ~ U ~ U U U ~ ~ --::l ~ U .4 U U U ~
~ X (~ 1 td a. a) o A ,L O h O O O ~ C I
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16 13 3 3 3 8 ~z jûSG/9537 Example 25 Preparation of 3~ oxohexyl)pyridine A solution of 10.8 g (62.1 mmol) of m-chloroperbenzoic acid in 120 ml of methylene chloride was added to a solu-tion of 3.9 g (21.1 mmol) of 2,2,6,6-tetramethyl-4-piperidone in 60 ml of methylene chloride at a tempera-ture of 25 C, and the mixture was stirred for ~0 min.
The solution was mixed with 120 ml of methylene chlo-ride, 300 ml of water, 3 g (25.2 mmol) of potassium bro-mide, 7.8 g (49.8 mmol) of sodium dihydrogen phosphate dihydrate, and 89.5 g (0.503 mol) of 3-(1-hydroxy-hexyl)pyridine. The pH of the aqueous phase was adjusted to 7.5 by the addition of hydrochloric acid or sodium hy-droxide solution. To the intensely stirred mixture 306 g of an aqueous solution containing 14% by weight of sodium hypochlorite (0.58 mol) was added dropwise. The mixture was stirred for another 30 min, then the pH of the reac-tion mixture was adjusted to 8.5.
The aqueous phase was separated and extracted twice with 150-ml portions of methylene chloride. The combined organic phases were treated as usual to isolate the ketone.
Yield: 73 b.p.: 90 C/0.3 mbar
Arhet~ll~Rl where Ar~t is a five-membered or six-membered heteroaro-matic radical having at least one nitrogen atom and R1 is hydrogen or an alkyl radical of from 1 to 20 carbon atoms, by oxidation of the corresponding 1-hydroxyalkyl compounds (II).
,, : Arhet~CH~
.
-~ 15 It is well known that aldehydes and ketones can be : prepared by oxidation of the corresponding primary or -~ secondary alcohols~
OH o R--CH--R Ox. R--C--R
The oxidation of al~phatic alcohols is usua,lly re~lativel,y easy, and many isoaromatic alcohols, for instance benzyl alcohol, are converted to the aldehydes simply by the ac--~ tion of atmospheric oxygen. The preparation of heteroaro-matic aldehydes from the appropriate hydroxymethyl com-:~ pounds presents some difficulties however; for example, to obtain pyridinecarbaldehydes, oxidants such as sele-- nium dioxide, lead tetraacetate, or manganese dioxide ~ 3 3 ~
~Z ~5G/3?'~?
~ .
have been used -- cf. Ullmanns Encyclop~die der technis-chen Chemie, 3rd ed., vol. 14, p. 478 (1963). Much the same can be said of heteroaryl alkyl ketones. For exam-ple, oxidation of the appropriate alcohols with chromium trioxide and sulfuric acid or with manganese dioxide has been used for the preparation of the particularly impor-tant pyridyl alkyl ketones -- cf. Deljac et al., Acta Pharm. Jugosl., 32(4), 267-74, Chem. Abstr., 98, 174241t, and ~S-A 4 098 908. Apart from the fact that the use of these expensive and physiologically somewhat dubious oxidants that have to be employed in solid form presents considerable technical difficulties, the yields and selectivities attained are mostly unsatisfactory.
It is known from the work of Anelli et al. -- J. Org.
Chem., 52, 2559-62 (1987) -- that some aliphatic and iso-aromatic alcohols can be successfully oxidized to the corresponding carbonyl compounds by sodium hypochlorite in the presence of potassium bromide and catalytic amounts of the piperidine derivatives R R R
O X~ 1H O
R = H; CH 3 X = Cl; ~r However, these workers make no mention of investigations relating to heteroaromatic hydroxymethyl compounds or heteroaromatic aldehydes and ketones.
The aim of the present invention was to make certain heteroaromatic aldehydes and ketones accessible in a sim-pler and more economic manner than hitherto. Accordingly we have found a process for the preparation of hetero-cyclic aromatic (heteroaromatic) aldehydes and ketones,ofthe general formula ~I), O
Arhet-C-R
(I) 3 13 313 8 3 ~z 0050j395~?
where Ar~t is a five-membered or six-membered heteroaro- :
matic radical having at least one nitrogen ato~ and R1 is hydrogen or an alkyl radical of from 1 to 20 carbon atoms, by oxidation of the corresponding 1-hydroxyalkyl compounds (II) IH ~:
Arhet-C~R
(II) wherein the oxidant is an inorganic or organic : hypochlorite or hypobromite (III) in conjunction with an ~
alpha,alpha,omega,omega-tetraalkylcycloalkane of the ~ :
general formula (IV), ~ ;~
(Y) , , ~ :-A I k~ A I k ( IV) : : where the radicals Alk are identical or different alkyls ~ 15 of from 1 to 4 carbon atoms, Q i5 one of the groups , ~
>N'=O X~ ; >N-OH or >N-O-(X- is an anion), n is either 0 or 1, and Y is oxygen, carbonyl, or >CR2R3; R2 and R3 are hydrogen, hydroxyl, or ~- organic radicals in which the free valency is attached to carbon or oxygen and that may be linked to form a five-~ . membered or six-membered,ring.
- We have also found that the reaction proceeds particu-larly successfully if it is carried out in the presence ~:: c of catalytic amounts of an inorganic bromide, if -- inde- :
pendent of the use of bromide -- it is carried out in a '~ two-phase system of water and an organic solvent, and if ::
- the pH is kept between 5 and 10. :~
;: , ,~ ~
1! ~ 3 ~ 3 8 3 oz ~OSC~3~7 The radical Ar~c in the product of the process (I) or :
the starting compound (II) corresponds to one of the fol~
lowing heteroaromatic systems (R4 is an alkyl of from 1 ~:
to 4 carbon atoms or benzyl):
~ ::
l4 pyrro e 1~3 ;'' R4 pyrazole ~l~ imidazole isoxazole oxazole ~:
1~
:: N`N-N
~; 15 14 1,2,3-triazole ~ :
~_N
N`~ 1, 2,4-triazole . R4 ~,~ 20 N~ 1, 2,3-oxadiazole ~N 1 ,2,4-oxadiazole ! ' j j j 1,2,5 oxadiazole N~N
N_N
~ 1,3,4-oxadiazole ~ ~ pyridine ,........................................................................ ..
' ~ ~
',.
..
~.
1 3 3 1 3 8 3 I7~~1~J5lJ,/'3587 ~ pyridazine N~
~NJ pyrimidine ¢~ ;
pyrazine In the starting compound (II) the 1-hydroxyalkyl group can be attached to any ring carbon atom. The remaining carbon atoms can carry any organic radical that is inert -- that is to say, non-oxidizable -- and in which prefer-ably a carbon atom has the free valency; examples of suchradicals are - alkyls of from 1 to 8 carbon atoms, such as methyl, ethyl, and isopropyl; ~ ~`
- cycloalkyls of from 3 to 12 ring carbon atoms, such~ ~
as cyclopentyl and cyclohexyl; ;~;
~ ~ .
- five-membered and six-membered oxacycloalkyls, such as 2-, 3-, and 4-oxacyclohexyl and 2- and 3-oxacyclopentyl;
- cycloalkylalkyls, such as 1-cyclohexylethyl and 2-cyclohexylethyl;
- aryls, such as phenyl, 1-naphthyl, and 2-naphthyl;
- arylalkyls, such as benzyl, 1-phenylethy}, and 2--~ phenylethyl;
- acyls R'-CO-, where R' is one of the radicals given above, such as acetyl and benzoyl;
- organyloxy radicals R'-O-, where R' is one of the alkyls, cycloalkyls, oxacycloalkyls, cycloalkyl-alkyls, aryls, or arylalkyls given above;
- oxycarbonyl radicals R'-O-CO-, such as methoxy-carbonyl and phenoxycarbonyl;
.~ -:
~ - carbonyloxy radicals R'-CO-O-, where R' is one of -~ the radicals defined above.
It is also possible for the oxazole, isoxazole, 1,2,3-- 35oxazole, 1,2,5-oxazole, and pyridine systems to form part '. '~
::
6 13 3 ~ 3 8 3 oz oGso/3ssa7 of fused systems, as in benzoxazole, benzisoxazole, and quinoline. The inert radicals named above can be them-selves substituted by fluoro, chloro, bromo, or cyano radicals, or by alkoxy radicals of from 1 to 4 carbon atoms. -The radical R1 can be hydrogen or an alkyl of from 1 to 20 carbon atoms.
The starting compounds (IIJ are known or can be ob- ~-tained by known methods. The hydroxymethylisoxazoles (IIa)-(IIc), which are particularly important because of the products they yield, can for instance be prepared as follows (R3 and R~ are organic radicals):
''-.
Me~CO~a~ H2NOHNaBH4 HO-CH2~3~R3 (lIa) -- cf. J. Org. Chem., 26, 1514 (1961) --,.
; R~ ~ o~e HzNOH LiAIH~ ~4 ~ CH2-CH
;~ (IIb) . ,:~
~ -- cf. ~er., 42, 3912 (1903) --, ::~
'- ~' , R3~ H R3 ~ CH2OH
(IIc) ~ -~
-- cf. DE-A 27 54 832 -~
- Something similar applies to the other starting compounds - (II).
The following are important starting compounds (II) -`
for the preparation of intermediates (I) that are used -~
for the synthesis of known crop protection agents (cf.
DE-A 36 09 181, for instance)~
,,. ~';,;
: ~ .
7 i33~ 383 1~ 050/3~58?
5-(hydroxymethyl)-3-methyIisoxazole --5-(hydroxymethyl)-3-ethylisoxazole 5-(hydroxymethyl)-3-propylisoxazole 5-(hydroxymethyl)-3-isopropylisoxazole :
5-(hydroxymethyl)-3-butylisoxazole 5-(hydroxymethyl)-3-isobutylisoxazole 5-(hydroxymethyl)-3-(sec-butyl)isoxazole 5-(hydroxymethyl)-3-(tert-butyl)isoxazole S-(hydroxymethyl)-3-(ethoxycarbonyl)isoxazole 5-(hydroxymethyl)-3-cyclopropylisoxazole 5-(hydroxymethyl)-3-cyclobutylisoxazole 5-(hydroxymethyl)-3-cyclopentylisoxazole ~.
5-(hydroxymethyl)-3-cyclohexylisoxazole 5-(hydroxymethyl)-3-(2-oxacyclohexyl)isoxazole 5-(hydroxymethyl)-3-(3-oxacyclohexyl)isoxazole :-5-(hydroxymethyl)-3-(4-oxacyclohexyl)isoxazole ~`
: 5-(hydroxymethyl)-3-(2-oxacyclopentyl)isoxazole 5-(hydroxymethyl)-3-(3-oxacyclopentyl)isoxazole 4-(hydroxymethyl)-3,5-dimethylisoxazole 3-(hydroxymethyl)-5-isopropylisoxazole ~:
5-(1-hydroxypentyl)-3-methylisoxazole ~` 5-(1-hydroxyhexyl)-3-(ethoxycarbonyl)isoxazole ::
1-benzyl-2-(:1-hydroxyhexyl)imidazole :
3-(hydroxymethyl)pyridine 2-(hydroxymethyl)pyridine ~~. 4-(hydroxymethyl)pyridine ~-~- 3-(1-hydroxyhexyl)pyridine :~
:~: 3-(2-ethyl-1-hydroxypentyl)pyridine ~:
~- 3-(1-hydroxypentyl)pyridine ~::
The oxldant is~an inorganic or organic hypochlorite or hypobromite tIII), referred to subsequently as the hypo-halite. Suitable inorganic hypohalites include sodium ~- hypochlorite in particular, but also potassium hypochlo- -~:~
;~ ~rite,, calcium hypochl,orite~ and sodium hypobromite; they : 35 are preferably employed as aqueous solutions, in which :
-~ the mass fraction of hypohalite is from about 5% to 20%, ~:~
''~- prepared from :the pure salts or by treating solutions of . ~ the alkali or alkaline-earth hydroxides with chlorine or ~-~: bromine. The most suitable organic hypochlorites and hy-pobromites are tertiary hypohalites, of which tert-butyl : .
hypochlorite is predominant.
,,, .
.:, , 3 1331 3830~ JC5u/J~C~' For complete oxidation of an alcohol (II) to a car-bonyl compound (I) it is necessar~ to use at least equimolar amounts of the hypohalite (III); generally it is recommended that the mole ratio of the excess amount of hypohalite (III) to the initial amount of alcohol should 'De Up to 50~. If either the alcohol (II) or the carbonyl compound (I) is very sensitive to oxidation it can be advisable to limit conversion by starting with less than the stoichiometric amount of hypohalite ~III), -equivalent to a mole ratio of roughly from 50% to 90 based on the initial amount of alcohol (II).
An essential feature of the novel oxidation process is the use of compounds of the general formula (IV), which function as catalytic oxygen transfer agents. These com-pounds are primarily the piperidine derivatives lIVa)~(IVc), Alk ~ ~ Alk Alk ~ ~ AlkAlk ~ ~ Alk Alk 11 Alk Alk I Alk Alk ~ Alk O Xe OH ~.
; IVa IVb IVc - of which the 2,2,6,6-tetramethyl derivatives are most im-portant because they are the most easily accessible. The nature of the group Y has only a secondary influence on the course of the reaction, and in principle almost any group is possible; however, for economic reasons the com-pounds (IV) are preferably simple ones in which the group ~ ;
Y is oxygen, carbonyl, methylene, 1,1-ethylene, hy-droxymethylene, or methoxymethylene.
The anion X~ can be almost any anion in principle, but for practical reasons sulfate, p-toluenesulfonate, ac-etate, and, above all, chloride and bromide are preferred. ~ i ' ! i` `
The piperidine derivatives (IVa)-(IVc) can be obtained by known methods -- cf. Synthesis, 191 (1971), for in-stance -- and are stable. They can be used as they are, but when together with a hypohalite (III) and the alcohol (II) that is to be oxidized they are interconverted in the course of the catalytic oxidation cycle; presumably the oxide ~IVa) is the immediate oxidizing agent. ;~
133~ 383 The piperidine d~rivatives (IVa)-(IVc~ can be empioyod direct or formed in situ by treating the appropriate piperidine compounds with an oxidizing agent. Suitable oxidizing agents are above all peroxides, such as hydro-5gen peroxide -- preferably accompanied by sodium tungstate or a similar compound of the o~ide of a metal in a high oxidation state --, especially organic perox-ides, such as m-chloroperbenzoic acid.
The remarks about the piperidine derivatives lIVa)-lO(IVc) apply analogously to the corresponding pyrrolidine compounds, so there is no need to discuss these separately.
The amount of compound (IV) used is optional in prin-ciple, but since catalytic action is required the mole 15ratio of the amount of compound (IV) to the initial amount of alcohol tII) is preferably from 0,1~ to 20~. If the ratio is less than 0.1~ the reaction proceeds too slowly, and a ratio greater than 20~ offers no worthwhile advantage.
20Since water is formed in the reaction, and the hypo-halite (III) is preferably employed in aqueous solution, there is always an aqueous phase. It is however advisable to provide an organic phase in which the organophilic re-;~ actants can dissolve and which will take up aldehydes (I) 25in particular and protect them to a certain extent from subsequent reactions; this is done by also using a solvent that is immiscible with water, such as methylene chloride, chloroform, ethyl acetate, butyl acetate, diethyl ether, or toluene. The quantity of this ~ 30immiscible solvent is not critical: generally it is from ;~ 1 kg to 10 kg per kilogram of alcohol (II).
It is also advantageous to adjust the pH of the aque-ous phase to a value between 5 and 10 and to keep this ~; value constant by means of a buffer such as sodium hydro-35gen carbonate, sodium acetate, or disodium hydrogen ph!os-phate. In more acid solutions the hypohalites (III) are less stable, and in strongly alkaline solution the alde-hyde lI) that is formed may take part in undesirable re-actions.
40The novel reaction is further promoted by bromide - ions, which are conveniently introduced as sodium or - potassium bromide, the mole ratio relative to the amount ~" ",," ,,,, "., "..,,","s ...",: .,." ,, ,,, ~ "",, ",, ~," ,,,,, -;",, ~ ,", ,"":-~;",: ,"; " ~ ~,", .
~f," . , .. ... ... , .. ,, ,. ,.,. ,, . - , ,,, -: : : . .. : :. :,.,:: ::. : .: :: .:.. -:.. .
lo 1 3 3 ~ 3 8 30z 00SU/~ j587 of alcohol (II) being from 1~ to 10~. No bromide needs to be added if the oxidant is hypobromite, since bromide ions are then formed anyway.
It is recommended that the reaction temperature is from 0 C to 100 C, preferably from 0 C to 40 ~C Gen-erally the process is carried out under atmospheric pres-sure or, if a volatile solvent is used, the vapor pres-sure of the reaction mixture.
It is technically convenient to mix all thé components except the hypohalite (III), so that a two-phase system is formed, then to add hypohalite gradually, say over a period of from 30 min to 10 h. Apart from this, the pro-cess has no technical peculiarities and needs no further description. The same applies to subsequent treatment of the reaction mixture, in the course of which the carbonyl compound (I) that is formed is isolated from the organic phase in the usual way. The aqueous phase left behind, which contains excess oxidant, catalysts, and buffer, can be used for further charges. Any hypohalite that remains in the organic phase can be destroyed by means of a re-ducing agent, such as iron(II) sulfate.
The yields of heteroaromatic aldehydes and ketones (I) are unexpectedly high: up to about 85%. The products are valuable intermediates for, inter alia, crop protection agents.
Example 1 Preparation of 5-formyl-3-(tert-butyl)isoxazole tI/1) Over a period of 3.5 h 1765 g of an aqueous solution con-taining 14~ by weight of sodium hypochlorite (3.3 mol) was added to an intensely stirred mixture of 465 g (3 mol) of 5-(hydroxymethyl)-3-(tert-butyl)isoxazole, 9.4 g (0.06 mol) of 2,2,6,6-tetramethylpiperidin-1-oxyl, 17.9 g (0.15 mol) of potassium !bromide, 46.8 g j(0.3 mol) of sodium dihydrogen phosphate dihydrate, 53.4 g (0.3 mol) of disodium hydrogen phosphate dihydrate, 1800 ml of methylene chloride, and 1800 ml of water at 20 C. During the whole of the reaction time the pH of the reaction mixture remained fairly constant between 6.5 and 7.5.
~.~
I 1 1 3 3 1 3 8 3 z 0050/~5~7 The organic phase was separated off and the aqueous phase extracted with methylene chloride. The combined or-ganic phases were washed with aqueous sodium hydrogen carbonate and treated as usual to isolate the aldehyde (I/1 ) .
Yield: 77~
b.p.: 82-4 C/0.01 mbar ~-m.p.: 42-3 C
Example 2 , ~
Preparation of 5-formyl-3-isopropylisoxazole (I/2) Over a period of 75 min 10.9 g (0.1 mol) of tert-butyl hypochlvrite was added to a stirred mixture of 14.1 g (0.1 mol) of 5-(hydroxymethyl)-3-isopropylisoxazole, 1.6 g (0.01 mol) of 2,2,6,6-tetramethylpiperidin-1-oxyl, 16.5 g (0.1 mol) of sodium dihydrogen phosphate dihydrate, 6Q
ml of methylene chloride, and 60 ml of water at 20 C, and the mixture was stirred for another 30 min. The pH
w~s about 8.
The aqueous phase was extracted with methylene chlo-ride, and the extract was combined with the original or--~ ganic phase, which was then washed successively with 30 -~ ml of dilute hYdrochloric acid, 30 ml of saturated aque-ous iron(II) sulfate solution, and sodium hydrogen car-~ 25 bonate solution. Finally the solution was treated as -~ usual to isolate the aldehyde (I/2).
Yield: 73%
`- b.p.: 74 C/4 mbar - 30 Example 3 Preparation of 5-fo~myl-3-isopropylisoxazole (I/2) A solution of 1.6 g (9.2 mmol) of m-chloroperbenzoic acid ~ in 25 ml of methylene chloride was added dropwise over a -- period of 15 min to a solution of 0.3 g (2.3 mmolj of 2,2,5,5-tetramethylpyrrolidine in- 10 ml of methylene chloride at a temperature of 20 C, and the mixture was stirred for a further 30 min.
':
12 l 3 3 ~ 3 8 3 Z ~050/39587 The catalyst solution prepared in this way was mixed with 40 ml of methylene chloride, 70 ml of water, 0.69 g ~5.8 mmol) of potassium bromide, 16.2 g (0.115 mol) of 5-(hydroxymethyl)-3-isopropylisoxazole, 1.8 g (11.5 mmol) of sodium dihydrogen phosphate dihydrate, and 2.0 g (11.5 mmol) of disodium hydrogen phosphate dihydrate. Over a period of 2 h 67.3 g of an aqueous solution containing 14% by weight of sodium hypochlorite (0.126 mol) was added to the intensely stirred mixture at 25 C, then the mixture was stirred for another 15 min.
The organic phase was separated off and the aqueous phase extracted with methylene chloride. The combined or-ganic phases were washed with aqueous sodium hydrogen carbonate and treated as usual to isolate the aldehyde (I/2)-Yield: 64~
Examples 4-24 Preparation of various aldehydes (I) General procedure (Example 4) To prepare a catalytically active piperidine derivative (IV) a solution of 25.9 g (0.15 mol) of m-chloroperben-zoic acid in 300 ml of methylene chloride was added over a period of 15 min to a solution of 9.3 g (0.06 mol) of 2,2,6,6-tetramethyl-4-piperidone in 150 ml of methylene chloride at a temperature of 20 C, and the mixture was stirred for a further 30 min.
The catalyst solution prepared in this way was mixed with 423 g (3 mol) of 5-(hydroxymethyl)-3-isopropylisoxa-zole, 18 g (0.15 mol) of potassium bromide, 46.8 g (0.3 mol) of sodium dihydrogen phosphate dihydrate, 53.4 g (0.3 mol) of disodium hydrogen phosphate dihydrate, 1350 ml of methylene chloride, and 1800 ml of water. Over a period of 4 h 1756 g of an aqueous solution containing 14~ by weight of sodium hypochlorite (3.3 mol) was added to the intensely stirred mixture at 25 C.
13 1 3 3 ~ 3 8 3 oz 005oi33s87 The same procedure was used in Examples 5-24, the subsequent treatment of the reaction mixture being as de-scribed in Example 1. In each case the pH was from 6.5 to : :
8Ø
5Details of these examples are given in the following table.
'-:
: ' ' ' ~ ~
., ~_ ~ " ~"" ~ " ~"~
;9~:s`~
-- 14 '1 3 3 ~. 3 8 ~ ,,050,39587 o I ~ ~ ~ o,~
h I O O O ~ ~ O ^i h ~: ~ o o I
h ~ 3 0 I td ~ I~ Q. Q, ~ X X ~ ~-- X
~ ~ 0 ~ ~ oa) '`I a~
I q) x Io d O O IQUl tJ T V1 ~: O O
' ~ ~ ' æ c~ ~ ~ æ ~ o ~ æ z : :~
tSI I h I ~ 1 1 o In o ~ I ~ I '::
I ~ I ~ I - - - -I~I IXX XXXX X
~ U , ~ oI ~ I ~ ~1 ~ o I ~ I
u l ~
:~
~:: l o l l ::
I Z H
. I I
I
';'`
~, ~ I I , '' ~ l l ' ~
. . ~ .
o o o o o o o ~, I I X X X X X X X--~ O
O O O O O O OO ~N
~ X O
: I I o~ oP Do. o~ o~ o~ oQ, .0~ ~~ ',:
O O aO oR o~ 04 oQ' L~
. I I I I I I I I I I I
~ H ~ E 6 e ~
H I X ~ X X ~ X X X X
i ~ g '~,::, I ~ I Ln L Ln Ln L~
n Ln Ln Ln Ln . l l .
. I I :
: I , . I :
n ~ o ~ ~ . .
.~
.
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o ,s~ , 4~ 1 , ~ ~r o ~ a) , m m m I
o a) a) a) ~ ~ ~ a) X x x I
Z C ~
Ia)X I O OOOOOOOOOOI
~ ~ ~ I æ z z z z z z z z æ ~
~r ~
I
~ l l O
t~ ~ O O ~ O N
I A I . . . . . o o o o o ~-- o o o o ~r o ~ I ~ -I ~ `1 X
o 1~1 o ~ ~ ~ ~ 1~ In o ~o o ~ r o o I
-:
H I ~
I U I '~
I ~ I I I ~
I O I ' I ~ ~
D~ I z H I ~ ~ _ ~ ~ ~ ~ ~
I
I
: - I I I :
O O
O O N N
O N N ~
N (1~ ~ ~¢ X
Xi ~ X O O
~q o ~ o u~
o ~ o t t~ N - -- -- O
N O ~
O ~-- ~ O ~ ~ ~ X td N
N :~ X In ~ 0 X
X O ~ -- ~ Q, Q. -~ O
O A O ~ O O
- I I -' ~ U ~ U U U ~ ~ --::l ~ U .4 U U U ~
~ X (~ 1 td a. a) o A ,L O h O O O ~ C I
O ~ I O I I I U ~ O ~
` I h h I H I e ~ e e e e E ~ e l~
~, I -- I X ~C X X ~ X X X X ~C X ~C I
- l l O O O O O O O O O O O O l .' ' h h h h h h h h h h h ~- I V I _ _ _ _ ~
X O ~ O ~ ~
16 13 3 3 3 8 ~z jûSG/9537 Example 25 Preparation of 3~ oxohexyl)pyridine A solution of 10.8 g (62.1 mmol) of m-chloroperbenzoic acid in 120 ml of methylene chloride was added to a solu-tion of 3.9 g (21.1 mmol) of 2,2,6,6-tetramethyl-4-piperidone in 60 ml of methylene chloride at a tempera-ture of 25 C, and the mixture was stirred for ~0 min.
The solution was mixed with 120 ml of methylene chlo-ride, 300 ml of water, 3 g (25.2 mmol) of potassium bro-mide, 7.8 g (49.8 mmol) of sodium dihydrogen phosphate dihydrate, and 89.5 g (0.503 mol) of 3-(1-hydroxy-hexyl)pyridine. The pH of the aqueous phase was adjusted to 7.5 by the addition of hydrochloric acid or sodium hy-droxide solution. To the intensely stirred mixture 306 g of an aqueous solution containing 14% by weight of sodium hypochlorite (0.58 mol) was added dropwise. The mixture was stirred for another 30 min, then the pH of the reac-tion mixture was adjusted to 8.5.
The aqueous phase was separated and extracted twice with 150-ml portions of methylene chloride. The combined organic phases were treated as usual to isolate the ketone.
Yield: 73 b.p.: 90 C/0.3 mbar
Claims (6)
1. A process for the preparation of heterocyclic aromatic (heteroaromatic) aldehydes and ketones of the general formula (I):
(I) where Arhet is a substituted or unsubstituted, five-membered or six-membered heteroaromatic radical having at least one nitrogen atom and R1 is hydrogen or an alkyl radical of from 1 to 20 carbon atoms, by oxidation of the corresponding 1-hydroxyalkyl compounds (II):
(II) wherein the oxidant is an inorganic or organic hypochlorite or hypobromite (III) in conjunction with an alpha, alpha, omega, omega-tetraalkylcycloalkane of the general formula (IV):
(IV) where the radicals Alk are identical or different alkyls of from 1 to 4 carbon atoms, Q is one of the groups:
>N+=O X- ; >N-OH or>N-O
(X- is an anion), n is either 0 or 1, and Y is oxygen, carbonyl, or >CR2R3 ; R2 and R3 are hydrogen, hydroxyl, or organic radicals in which the free valency is attached to carbon or oxygen and that may be linked to form a five-membered or six-membered ring.
(I) where Arhet is a substituted or unsubstituted, five-membered or six-membered heteroaromatic radical having at least one nitrogen atom and R1 is hydrogen or an alkyl radical of from 1 to 20 carbon atoms, by oxidation of the corresponding 1-hydroxyalkyl compounds (II):
(II) wherein the oxidant is an inorganic or organic hypochlorite or hypobromite (III) in conjunction with an alpha, alpha, omega, omega-tetraalkylcycloalkane of the general formula (IV):
(IV) where the radicals Alk are identical or different alkyls of from 1 to 4 carbon atoms, Q is one of the groups:
>N+=O X- ; >N-OH or>N-O
(X- is an anion), n is either 0 or 1, and Y is oxygen, carbonyl, or >CR2R3 ; R2 and R3 are hydrogen, hydroxyl, or organic radicals in which the free valency is attached to carbon or oxygen and that may be linked to form a five-membered or six-membered ring.
2. A process as claimed in claim 1, wherein the radical Arhet in the compounds (I) and (II) is unsubstituted or substituted isoxazolyl, pyridyl or pyrimidinyl.
3. A process as claimed in claim 1 or 2, carried out in the presence of sodium or potassium bromide.
4. A process as claimed in claim 1 or 2, wherein the reaction is carried out in a two-phase system comprising water and an organic solvent.
5. A process as claimed in claim 1 or 2, wherein the reaction is carried out with a pH of from 5 to 10.
6. A process as claimed in claim 1 or 2, wherein the compound (IV) is prepared in situ from the appropriate pyrrolidine or piperidine and an oxidizing agent.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19873738909 DE3738909A1 (en) | 1987-11-17 | 1987-11-17 | METHOD FOR PRODUCING HETEROCYCLIC-AROMATIC ALDEHYDES |
| DEP3738909.2 | 1987-11-17 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1331383C true CA1331383C (en) | 1994-08-09 |
Family
ID=6340617
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000583240A Expired - Lifetime CA1331383C (en) | 1987-11-17 | 1988-11-16 | Preparation of heterocyclic aromatic aldehydes and ketones |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP0316783B1 (en) |
| CA (1) | CA1331383C (en) |
| DE (2) | DE3738909A1 (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0710806B2 (en) * | 1989-07-28 | 1995-02-08 | 株式会社クラレ | Method for producing α-ketocarboxylic acid ester |
| US5194606A (en) * | 1990-02-08 | 1993-03-16 | Mitsui Toatsu Chemicals, Incorporated | Preparation process of aminoketones |
| US5055585A (en) * | 1990-02-08 | 1991-10-08 | Mitsui Toatsu Chemicals, Incorporated | Preparation process of aminoketones |
| EP0446798B1 (en) * | 1990-03-13 | 1994-11-23 | Hoechst-Roussel Pharmaceuticals Incorporated | 1-alkyl-, 1-alkenyl- and 1-alkynylaryl-2-amino-1, 3-propanediols and related compounds, a process and intermediates for their preparation and their use as medicaments |
| GB2404190A (en) * | 2002-03-26 | 2005-01-26 | Koei Chemical Co | Process for producing heterocyclic aldehyde |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6034546B2 (en) * | 1978-03-09 | 1985-08-09 | 大鵬薬品工業株式会社 | Glyoxal-2-oxime derivative and method for producing the same |
-
1987
- 1987-11-17 DE DE19873738909 patent/DE3738909A1/en not_active Withdrawn
-
1988
- 1988-11-11 DE DE8888118788T patent/DE3869335D1/en not_active Expired - Lifetime
- 1988-11-11 EP EP88118788A patent/EP0316783B1/en not_active Expired - Lifetime
- 1988-11-16 CA CA000583240A patent/CA1331383C/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| EP0316783B1 (en) | 1992-03-18 |
| EP0316783A1 (en) | 1989-05-24 |
| DE3869335D1 (en) | 1992-04-23 |
| DE3738909A1 (en) | 1989-05-24 |
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