Preparation of allylic aromatic compounds

Details Preparation of allylic aromatic compounds Preparation of allylic aromatic compounds

1999-12-17

2001-09-04

Barts, Samuel (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C560S020000, C560S254000, C562S437000, C564S305000, C568S306000, C568S584000, C568S932000, C568S933000, C568S936000, C568S937000, C568S939000, C568S940000, C570S182000, C570S200000

Reexamination Certificate

active

06284894

ABSTRACT:

This invention is concerned with the preparation of allylic aromatic compounds.
A number of methods are known for the introduction of an allylic group into an aromatic compound, such as cross-coupling or direct allylation, but these often require the use of expensive and toxic metal reagents or catalysts, e.g. Sn or Pd, or air (oxygen) and water sensitive reagents and substrates which are difficult to work with on a large scale. It has often been shown that aromatic compounds substituted with electron withdrawing groups produce allylated products after extended reaction times and in reduced yield. Allylation of an aromatic carbon via a radical intermediate (e.g. a phenyl radical) has also been proposed (e.g. Migita et al., Bull. Chem. Soc. Jpn, 56, 2480-2484 (1983)), but these reactions require either at least two process steps and unstable and toxic intermediates or the use of toxic tin catalysts.
These methods are therefore unsuitable for use on a large scale, particularly in the manufacture of compounds required as intermediates for use in the production of medical products. An important example of an allylic compound of this kind is allyl-3,5-dinitrobenzene, which can be used in the production of iodinated X-ray contrast agents containing dihydroxypropyl side chains, such as described in WO 96/09282.
We have now found a new method of preparing allylic aromatic compounds such as allyl-3,5-dinitrobenzene which can give the required product in high yield from commercially available and less hazardous starting materials without the use of metal reagents or catalysts. The procedure is more convenient in that only a single process step is required and the reaction time is short. The method is therefore suitable for use for large scale manufacture.
The invention thus provides a process for the preparation of an allylic aromatic compound in which an aromatic amine is reacted first with a nitrite and then with an allylic olefin having an eliminatable terminal substituent.
The aromatic amine starting material may for example be substituted by one or more (and preferably two) electron withdrawing groups and may have the formula R—NH
2
where:
R is a phenyl or heterocyclic aromatic group optionally substituted by one or more of the following groups: OH, OX, OCN, OCOX, OCONH
2
, OSO
2
H, OSO
2
X, OSiX
3
, OPOX
2
, X, CHO, COX, COOH, COOX, CONHZ, CONX
2
, CN, NO
2
, NCO, NCS, NC, NHZ, NX
2
, NZOH, NZCHO, NZCOX, NZCO
2
X, NZCONH
2
, NZSO
2
X, SH, SX, SOX, SO
2
X, SO
2
NHZ, SO
2
NX
2
, SCN, F, Cl, Br, B(OH)
2
, B(OX)
2
, or PO(OX)
2
;
X is a phenyl or C
1
-C
10
alkyl group optionally substituted by F, Cl, Br and/or substituents containing F, Cl, Br, O, S or N (such as halo-C
1-3
alkyl, C
2-6
alkanoyloxy, C
1-6
alkoxy, OH, OCN, OCONH
2
, OSO
2
H, CHO, COOH, CONH
2
, NC, NO
2
, NCO, NCS, CN, NH
2
, SH, SO
2
NH
2
or SCN);
X
2
represents two X groups or a C
3-8
cycloalkyl group optionally substituted as defined for X, for example, F, Cl and/or Br; and
Z is H or X.
When R is a heterocyclic group, it may contain O, N or S as the heteroatom and may be monocyclic or bicyclic.
The aromatic amine preferably has the formula (1)
where:
R
1
, R
3
and R
5
are independently H or NO
2
, and R
2
and R
4
are independently H, NO
2
, COOH, COOMe, COOEt, CONH
2
, CONX
2
, COMe, CN or CF
3
, provided that at least one (and preferably at least two) of R
1
-R
5
is other than H.
Examples of suitable amines are 3-nitroaniline, 4-nitroaniline, 2,4-dinitroaniline, 2,6-dinitroaniline, 3,5-dinitroaniline, 3-acetyl-5-nitroaniline, 3,5-diacetylaniline, 3-carboxymethyl-5-nitroaniline, 3-carboxyethyl-5,-nitroaniline, 3,5-dicarboxyethylaniline, 3,5-dicarboxymethylaniline and 3,5-bisaminocarbonylaniline.
A preferred amine starting material is 3,5-dinitroaniline.
The nitrite used may be an organic nitrite such as a C
1-6
alkyl nitrite, preferably t-butylnitrite, or an aromatic nitrite.
The allylic olefin reagent may be a compound of the formula R
a
L where R
a
is a 2,3-alkenyl group (such as a C
3-6
alkenyl or C
5-7
cycloalkenyl group which may be optionally substituted) and L is an eliminatable substituent.
The allylic reagent may for example have the formula (2)
where L is Br, I, SR
b
, SnR
b
3
, SiR
b
3
, Si(TRS)
3
, SSi(TRS)
3
, SSnR
b
3
, SO
2
R
b
, SO
2
CF
3
, SePh or OPO(OPh)
2
(where TRS is trialkylsilyl and R
b
is C
1-6
alkyl, C
2-6
alkenyl or aryl such as phenyl or tolyl), and
R
1
-R
4
,independently, is each a hydrogen atom or a phenyl or C
1
-C
10
alkyl group optionally substituted by F, Cl, Br and/or substituents containing F, Cl, Br, O, S, N such as given above for X. R
1
and R
3
may also be Br or —COOH Examples of such compounds are 3-bromopropene, 3-bromo-2-methylpropene, 2-bromomethylacrylic acid, 2-acetoxymethyl-3-bromopropene, 1,4-dibromo-2-butene, 1-acetoxy-4-bromo-2-butene, 1-hydroxy-2-bromo-3-butene, 1-acetoxy-2-bromo-3-butene, allyldisulfide, allylsulfide, allylmethylsulfide, allyliodide and allyl bromide.
It is believed that in the initial stage of the reaction, the nitrite diazotises the aromatic amine and forms an aryl radical which then reacts with the allylic reagent R
a
L to produce the required allylic aromatic compound by elimination of the substituent L.
In reactions where the allylic reagent and/or the nitrite are liquid it is not necessary to use a solvent, but a polar solvent such as acetonitrile or dimethyl-sulphoxide can be used if required. The reaction temperature is preferably kept relatively low (e.g. 5-15° C.), and if desired can then be increased to 20-40° C., conveniently room temperature, to ensure that the reaction is completed.
As indicated above, the process of the invention is particularly suitable for the preparation of 1-allyl-3,5-dinitrobenzene, which is a new compound and is a further aspect of the invention. The preparation is preferably conducted by reaction of 3,5-dinitroaniline with t-butylnitrite and allyl bromide, using the allyl bromide and the nitrite as the reaction solvent. The reaction can be completed within 2-2.5 hours to give a yield of over 90% of the required compound, and is suitable for large scale use. This compares very favourably with the use of toxic and expensive tin catalysts. Thus, direct allylation of 3,5-dinitroiodobenzene with tributylallyltin in the presence of a palladium complex catalyst only gave a yield of 20% after a reaction time of one week.
The following examples illustrate the invention.


REFERENCES:
patent: 5475176 (1995-12-01), Beller et al.
Jacek Porwisiak and Manfred Schlosser, “1-Bromo-3,5-bis(trifluoromethyl)benzene: A Versatile Starting Material for Organometallic Synthesis”, Chem. Ber, 1996, XP002133846.
Migita, T. et al., “SH′ Type Reactions of Substituted Allylic Compounds”, Tetrahedron, 1973.
Kiyoshige Takayama et al., “Reactivities of Aryl Radicals in Hydrogen Abstraction and Addition”, Chemistry Letters, 1973.
Migita, T. et al., “Relative Reactivities of Substituted Phenyl Radicals in Elementary Reactions”, 1979, J.C.S. Perkin II.
Migita, T. et al., Free Radical Chain Reaction of Allylic Tin Compounds with Organic Halides Involving SH′ Process, 1983, The Chemical Society of Japan.
Al Adel, I. et al., Bulletin de la Societe Chimique de France partie II-Chimie Moleculaire Organique et biologique, 1976, 5-6, 934-938.
M.P. Doyle et al., “Alkyl Nitrite-Metal Halide Deamination Reactions. 3. Arylation of Olefinic Compounds in the Deamination of Arylamines by Alkyl Nitrites and Copper (II) Halides. A Convenient and Effective Variation of the Meerwein Arylation Reaction”, 1977, J. Org. Chem.

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