Aromatic hydroxythiol synthesis using diazonium salts

Details Aromatic hydroxythiol synthesis using diazonium salts Aromatic hydroxythiol synthesis using diazonium salts

2000-02-29

2001-10-16

Vollano, Jean F. (Department: 1621)

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

Organic compounds

Sulfur containing

C568S021000

Reexamination Certificate

active

06303822

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to the preparation of aromatic hydroxythiol compounds, and, more specifically, to the preparation of isomerically pure hydroxythiophenols. In particular, the present invention relates to a commercially feasible hydroxythiophenol synthesis in which significant quantities of the isomerically pure reaction product are obtained.
DESCRIPTION OF THE PRIOR ART
Diazonium salt reactions are generally employed to substitute an aromatic ring with a hydroxyl group. The diazonium salt reaction of aromatic thiols, however, produces a poor yield of diazonium salt. Furthermore, aromatic thiols are nucleophiles that tend to react violently with diazonium reagents.
Isomerically pure hydroxythiophenols are important reagents and starting materials for a variety of pharmaceutical, agrochemical and chemical processes. 3-Hydroxythiophenol, in particular, has been used as a key starting material for the synthesis of a new drug for the prevention of breast cancer. The commercial demands for these compounds have created a need for their practical large scale production.
An isomerically pure hydroxythiophenol could be prepared by reacting an isomerically pure aminothiophenol with NaNO
2
and H
2
SO
4
to form the corresponding diazonium salt, which could then be converted to a hydroxythiophenol by reaction with water. However, consistent with other aromatic thiol compounds, low yields are obtained. There remains a need for a commercially practical method of producing isomerically pure hydroxythiophenols in high yield.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
This need is met by the present invention. It has now been discovered that oxidation of aromatic thiols to create a disulfide linkage between two thiol groups eliminates the reactivity of the thiol sulfur toward diazonium reagents. The use of the disulfide structure as an internal self-protecting group eliminates the need for additional reagents for carrying out protection of the thiophenol group. This is particularly advantageous for the production of isomerically pure hydroxythiophenols.
Furthermore, many of the process steps can be performed in one pot, without the intervening extraction and washing steps. Species are not formed by de-protection of the thiophenol that would require removal in an additional washing step.
The present invention thus provides an improved method the preparation of aromatic hydroxythiol compounds in which, as shown in Step I, an aromatic aminothiol compound is oxidized to form an aromatic aminodisulfide:
Step I
2 H
2
N—Ar—SH{right arrow over (oxidant)}H
2
N—Ar—S—S—Ar—NH
2
Ar is selected from aryl, aralkyl or heterocyclic rings or a fused ring structure of from two to ten of such rings. The bis-diazonium salt of the aromatic aminodisulfide is then formed, as shown in Step II, by treating the aromatic aminodisulfide with NaNO
2
and H
2
SO
4
:
Step II
H
2
N—Ar—S—S—Ar—NH
2
{right arrow over (NaNO
2
+L /H
2
+L SO
4
+L )}X
−+
N
2
—Ar—S—S—Ar—N
2
+
X
−
The bis-diazonium salt is then reacted with water, as shown in Step III, to form an aromatic hydroxyldisulfide compound:
Step III
X
−+
N
2
—Ar—S—S—Ar—N
2
+
X
−
{right arrow over (H
2
+L O)}HO—Ar—S—S—Ar—OH
The disulfide bond is then reduced, as shown in Step IV, to obtain the aromatic hydroxythiol compound:
Step IV
HO—Ar—S—S—Ar—OH{right arrow over (Reducing Agent)}2 HO—Ar—SH
Because the reaction itself does not generate isomers, the method of the present invention is useful for the synthesis of isomerically pure aromatic hydroxythiol compounds, and particularly useful for the synthesis of isomerically pure hydroxythiophenol compounds. Hydroxythiophenol synthesis is depicted in Steps I-IV when Ar is an unsubstituted or substituted phenyl group.
For purposes of the present invention, an “isomerically pure” reaction product contains the same level of isomeric impurities as its starting material. Therefore, with the method of the present invention, the isomeric purity of the reaction product will depend upon the isomeric purity of its starting material, and it is possible to obtain an isomeric purity of 95 wt % and greater. Thus, to obtain an isomerically pure end product, an isomerically pure starting material must be employed.
Another aspect of the present invention provides bis-diazonium salt compounds having the structure depicted in Formula I:
X
−+
N
2
—Ar—S—S—Ar—N
2
+
X
−
  (I)
Both Ar groups are the same and are selected from divalent substituted or unsubstituted aromatic radicals, divalent substituted or unsubstituted araliphatic radicals, divalent substituted or unsubstituted heterocyclic radicals and fused ring structures formed therefrom containing from two to ten rings.
The method of the present invention utilizes aromatic aminothiol compounds as starting materials. The compounds are commercially available. Alternately, they may be prepared using essentially conventional techniques. Aromatic aminothiol starting materials suitable for use with the present invention have the structure of Formula II:
H
2
N—Ar—SH  (II)
Ar is as described above for Formula I. More preferably, Ar is a substituted or unsubstituted C
6
-C
15
aryl radical, a substituted or unsubstituted C
7
-C
13
aralkyl radical, a substituted or unsubstituted 3-6 member heterocyclic radical, or a two or three ring fused ring structure of any of the foregoing. Essentially any substitution groups that are inert toward diazonium salt-forming reagents or are capable of being protected from reaction with diazonium salt-forming reagents may be employed. Suitable substitution groups, substitution groups requiring protecting groups, protecting groups and methods of protection are well-known. Examples of substitution groups include C
1
-C
6
aliphatics such as alkyls, alkoxys and alkenyls, C
6
-C
15
aryls, C
3
-C
8
cyclic aliphatics, amidos and secondary and tertiary aminos.
Ar as a 3-6 ring member heterocyclic radical may include known heterocyclic atoms such as N, O and S. Suitable heterocycles include, for example, pyran, thiophene, pyrrole, furan, pyridine, or derivatives thereof. Ar as a C
6
-C
15
aryl may be, for example, phenyl, o-tolyl, m-tolyl, p-tolyl, o-xylyl, m-xylyl, p-xylyl, alpha-naphthyl or beta-naphthyl. Ar as a C
7
-C
20
aralkyl radical may be, for example, benzyl, 4-methylbenzyl, o-methylbenzyl, p-methylbenzyl, diphenylmethyl, 2-phenylethyl, 2-phenylpropyl or 3-phenylpropyl, and preferably a C
7
-C
9
aralkyl, especially benzyl. Any of these groups may be substituted, for example, with substituted or unsubstituted, straight-chained or branched C
1
-C
20
alkyl, aryl, aralkyl, amido, alkoxyl and secondary and tertiary amino groups.
In a preferred embodiment, Ar is C
6
-C
14
aryl, especially phenyl or naphthyl. When the aryl or aralkyl group of Ar is a phenyl or alkylphenyl group the compound of Formula II is a starting material for hydroxythiophenols having the structure of Formula III:
Y is selected from straight-chained or branched, unsubstituted or substituted C
1
-C
20
alkyl, aryl, aralkyl, amido, alkoxyl and secondary and tertiary amino groups; and n is between 0 and 4, inclusive.
The aromatic aminothiol starting materials can be obtained commercially, or, as shown below, by reducing corresponding aromatic nitrosulfonyl chlorides:
Scheme I
O
2
N—Ar—SO
2
Cl{right arrow over (Reducing Agent)}H
2
N—Ar—SH
Essentially any well-known reagent capable of reducing an aromatic nitrosulfonyl chloride to an aromatic thiophenol can be used. Suitable reagents, solvents and process conditions may be determined by reference to March, J.,
Advanced Organic Chemistry
(2
nd
Ed., McGraw-Hill,1977), (the disclosure of which is incorporated herein by reference) and through routine optimization of reaction parameters. Examples of suitable reducing agents include hydroiodic acid, metal/concentrated mineral acid combinations such as Zn, Sn or Fe and concentrated hydrochloric or sulfuric acid, or hydrides such as NaBH
4
or LiAlH
4
.
The aromatic aminothiol starting

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