Synthesis of hydroxylamines using dioxiranes

The subject invention relates to a method of synthesizing hydroxylamines from secondary amines. This method uses a dioxirane compound such as dimethyldioxirane (DMD, which is relatively stable and simple to synthesize), as the oxidizing agent. The reaction proceeds as follows: ##STR1## This method provides a simple, one-step reaction with high yields. It can be performed in acetone solution, and the transferral of an oxygen atom from dimethyldioxirane to the secondary amine converts the dioxirane into acetone, the solvent, permitting simple workup and purification. This method can be used with a wide variety of secondary amines, including aliphatic, aromatic, cyclic, and heterocyclic secondary amines, to create a corresponding variety of hydroxylamines.

FIELD OF THE INVENTION 
This invention is in the field of organic chemistry, and relates to the 
synthesis of hydroxylamines of secondary amines. 
BACKGROUND OF THE INVENTION 
Dioxirane compounds have the following structure: 
##STR2## 
Before it was isolated or proven to exist, Montgomery 1974 and Edwards 1979 
(full citations are provided below) speculated that dimethyldioxirane 
(DMD) was present in certain reactions they were studying. DMD was first 
isolated by Robert W. Murray (one of the co-inventors of the subject 
invention) and his coworkers, and a method for synthesizing DMD in acetone 
solution is described in Murray et al 1985 (full citations are provided 
below). DMD can be synthesized in acetone solution at relatively low cost, 
and stored in a conventional freezer at about 0.degree. C. for up to about 
a week with little or no degradation. 
Various other dioxiranes have also been created, including 
methylethyldioxirane and diethyldioxirane (Murray 1985) and 
trifluoromethylmethyldioxirane (Mello et al 1988). 
Dioxiranes are powerful oxidizing agents. For example, DMD has been used to 
oxidize primary amines, forming nitro compounds (Murray et al 1986). Eaton 
et al 1988 reported that dioxirane can be used to oxidize sensitive 
primary amines if the amine hydrochloride rather than the free amine is 
used. Zabrowski et al 1988 reports the use of dioxirane to oxidize 
substituted anilines to form nitro compounds. Prior to the subject 
invention, they had not been used to create hydroxylamines. 
Hydroxylamines 
Hydroxylamines derived from secondary amines are useful as intermediates in 
a variety of reactions. For example, they are used in the synthesis of 
nitrones which are used commercially as spin traps (Evans 1979), in the 
synthesis of nitroxides which are important as spin labels in probing 
biological structures (Berliner 1976 and Holtzman 1984), and as magnetic 
resonance imaging (MRI) contrast-enhancing agents (Keana et al 1985). 
Some hydroxylamines also have direct utility. For example, heterocyclic 
hydroxylamines have various pharmacological and physiological activities. 
Some central nervous system depressants exhibit more activity in 
hydroxylamine form than in their amino or N-aryloxy derivatives (Klioze et 
al 1977). Sterically hindered hydroxylamines are used as bioantioxidants 
(Komoroy et al 1987), as inhibitors of lipid peroxidation (Zhdanoy et al 
1988), and as suppressors of plant tumor growth (Serebryanyi et al 1985). 
In the polymer industry, hydroxylamines are used as polymerization 
inhibitors for dienes (Japanese Patent JP 61,130,242; Chem Abstr. 105: 
173217r, 1986) and for vinyl aromatic monomers (US patent 4,409,408, 
Miller). They are also used to stabilize polyolefins (Seltzer et al, APO 
appln. 138,767; Chem Abstr. 103: 72145u, 1985) and to prevent the 
premature oxidation of leuco dyes in photoimaging compounds (US patent 
4,298,678, McKeever). Hydroxylamines have been used as catalysts in the 
facile hydration of nitriles to amides (Miyazawa et al 1964), and 
N,N-dialkyl hydroxylamines have been shown to be useful as precursors for 
synthesizing nitrenium ions (Gassman et al 1973). 
Previous Methods of Synthesizing Hydroxylamines 
Various methods have been reported for synthesizing hydroxylamines. For 
example, 2-(phenylsulfonyl)-3-aryloxaziridines (Davis et al 1986) can be 
used to synthesize hydroxylamines using secondary amine reagents (Zajac et 
al 1988). The hydroxylamines formed by that process are accompanied by 
varying amounts of nitrones. Gribble et al 1977 describes a general 
synthesis of hydroxylamines in which the corresponding oxime is reduced 
with sodium borohydride or lithium aluminum hydride. The oxidation of 
secondary amines with hydrogen peroxide gives hydroxylamines, but the 
yields are poor (Wolfenstein 1892; Henry et al 1950). Hydroxylamines are 
also available from the pyrolysis of tertiary amine oxides (Cope et al 
1949; Rogers 1955). 
Sterically hindered hydroxylamines are prepared via the reduction of 
corresponding nitroxides, using a variety of reducing agents (Paleos et al 
1977; Rozantsey et al 1964 and 1966; Le.RTM.et al 1975; Dadonneau et al 
1984). The drawback of such methods is that the nitroxides are often 
difficult to synthesize. Several groups have described the reduction of 
nitrones to hydroxylamines (Exner 1955; Hortmann et al 1978; Hammer et al 
1964; Delpierre et al 1965). 
The most common method of preparing hydroxylamines is the oxidation of a 
corresponding amine with benzoyl peroxide (Gambarajan 1925 and 1927; 
Biloski et al 1983). This method requires treatment of an intermediate 
0-benzoylated hydroxylamine with base in order to obtain the free 
hydroxylamine. In a similar procedure developed by Sturtz and coworkers, 
an amine is oxidized with bis[diphenylphosphinyl]peroxide, creating an 
intermediate 0-diphenylphosphinyl-hydroxylamine, and the hydroxylamine is 
obtained by acidic hydrolysis of that intermediate (Yaouanc et al 1985). 
While that method generally gave good yields of hydroxylamines, it 
involved a two step process. In addition, Yaouanc et al 1985 reported that 
there was no generally reliable methodology for oxidizing secondary amines 
to form N,N-dialkylhydroxylamines. 
Thus, the previously known methods of synthesizing hydroxylamines suffer 
from various limitations. Most previous methods of synthesis require 
multi-step reactions; they tend to suffer from low yields, and from 
unwanted by-products which may be very difficult yet necessary to remove 
before the desired hydroxylamines can be used for biological purposes. In 
addition, the prior methods of synthesizing hydroxylamines often require 
reagents that are expensive and/or difficult to synthesize. 
The present invention, by contrast, provides a general method for 
synthesizing hydroxylamines from secondary amines. This method offers a 
simple, one-step process with very high yields and little or no unwanted 
by-products. It has been shown to work satisfactorily with different types 
of secondary amine reagents, including aliphatic, aromatic, cyclic, and 
heterocyclic secondary amines. With each type of reagent, the secondary 
amine group is attacked very selectively; therefore, there is no need to 
take special steps to protect and then deprotect other reactive groups. 
SUMMARY OF THE INVENTION 
The subject invention relates to a method of synthesizing hydroxylamines 
from secondary amines. This method uses a suitable dioxirane compound, 
such as dimethyldioxirane (DMD, which is relatively stable and simple to 
synthesize) as the oxidizing agent. The reaction proceeds as follows: 
##STR3## 
This method provides a simple, one-step reaction with high yields. It can 
be performed in acetone solution, and the transferral of an oxygen atom 
from the dioxirane to the secondary amine converts the dioxirane into 
acetone, the preferred solvent, permitting simple workup and purification. 
This method can be used with a wide variety of secondary amines, including 
aliphatic, aromatic, cyclic, and heterocyclic secondary amines, to create 
a corresponding variety of hydroxylamines. 
DETAILED DESCRIPTION OF THE INVENTION 
The subject invention involves the use of dioxirane compounds to convert 
secondary amines to their corresponding hydroxylamines. 
The specific dioxirane compound used in the Examples is dimethyldioxirane 
(DMD). That particular derivative is used because (1) it is relatively 
simple and inexpensive to synthesize, (2) it is sufficiently stable for 
use in the subject invention, and (3) DMD yields a preferred solvent, 
acetone, rather than an undesired byproduct when it loses an oxygen atom. 
If desired, other dioxirane derivatives can be synthesized and used 
instead of dimethyldioxirane to convert secondary amines into 
hydroxylamines. Unless such other dioxirane derivatives are deliberately 
provided with highly reactive groups at other locations on the molecule, 
which might cause competing reactions, the dioxirane structure will react 
quickly and selectively with secondary amine groups to form 
hydroxylamines. 
Table 1 summarizes the yields of several reactions described in the 
Examples. The compounds listed in Table 1 can serve as precursors for 
synthesizing nitroxides which have major commercial significance. 
TABLE l 
______________________________________ 
Yields of Hydroxylamines Which Can Serve As 
Precursors For Major Nitroxides 
Yield 
Hydroxylamine (%) 
______________________________________ 
1,4-dihydroxy-2,2,6,6-tetramethyl piperidine 
99 
4-hydroxy-3,3-dimethyl-1-oxa-4-azaspiro [4.5] decane 
96.2 
4-hydroxy-3,3-dimethyl-1-oxa-4-azaspiro [4.6] undecane 
97 
3'-hydroxy-4',4'-dimethylspiro-(5.alpha.-cholestane-3,2'- 
97 
oxazolidine) 
1-hydroxy-2,2,5,5-tetramethyl-pyrroline-3-carboxamide 
______________________________________ 
The yield of 1-hydroxy-2,2,5,5-tetramethyl-pyrroline-3-carboxamide was not 
determined, because it is spontaneously oxidized by air. If desired, it 
can be created under a blanket of inert gas and in the absence of light, 
to avoid aerial oxidation. 
Table 2 lists the yields of several other hydroxylamines which do not have 
large commercial markets at the present time. The subject invention, by 
providing a method of synthesizing those compounds at lower expense and 
higher yield, is likely to stimulate greater use of those compounds as 
well as other similar or related compounds. 
TABLE 2 
______________________________________ 
Yields of Other Hydroxylamines 
Hydroxylamine Yield (%) 
______________________________________ 
N-hydroxy-N-tert-butyl benzylamine 
99.6 
N,N-dibenzylhydroxylamine 
98 
N-hydroxy-N-tert-butyl-N-p-nitrobenzylamine 
93 
N,N-diisobutylhydroxylamine 
97.4 
N,N-dicyclohexylhydroxylamine 
82.6 
______________________________________ 
Table 3 lists hydroxylamines synthesized by the methods of this invention, 
which had never been previously reported to exist. To the best of the 
applicants' knowledge, this is the first time these compounds have ever 
been created. 
TABLE 3 
______________________________________ 
Hydroxylamines Which Were Not Previously Reported 
______________________________________ 
4-hydroxy-3,3-dimethyl-1-oxa-4-azaspiro [4.5] decane 
96.2 
4-hydroxy-3,3-dimethyl-1-oxa-4-azaspiro [4.6] undecane 
97 
3'-hydroxy-4',4'-dimethylspiro-(5.alpha.-cholestane-3,2'- 
97 
oxazolidine 
______________________________________ 
The equipment assembly 10 for creating the dimethyldioxirane used to carry 
out the method of this invention is shown in FIG. 1. The reaction vessel 
comprises a three-necked flask 12, wherein the three necks serve as inlets 
14 and 16 and outlet 18. A magnetic stirring bar 20 is placed in the 
reaction vessel 12; it is rotated by a magnetic stirrer 22. 
The reaction vessel 12 is initially charged with a mixture of acetone, 
water, and sodium bicarbonate. It is kept at room temperature during the 
DMD synthesis. 
A liquid addition unit 30 with a stopcock 32 and a pressure equalizer 34 is 
coupled to inlet 14 of reaction vessel 12 via a Y-tube 36. A continuous 
supply of gaseous helium (an inert gas used as a carrier for the gaseous 
DMD) is provided to reaction vessel 12 via the other inlet provided by 
Y-tube 36. The helium is injected into the bottom region of reaction 
vessel 12 via tube 38. The inert carrier gas should be injected below the 
surface of the liquid, and can be dispersed throughout the reaction vessel 
by a dispersing nozzle or manifold on the bottom of the vessel. 
Second inlet 16 of reaction vessel 12 is coupled to a vessel 40 which 
contains Oxone (a trademark of DuPont), a formulation containing 
monoperoxysulfuric acid, 2KHSO.sub.5 .multidot.KHSO.sub.4 
.multidot.K.sub.2 SO.sub.04. The vessels are coupled via a device such as 
a flexible tube 42 which allows the Oxone (in granular form) to be added 
slowly to reaction vessel 12. 
Outlet 18 of reaction vessel 12 is coupled to vapor column 50, which is 
packed with glass wool 52 to prevent any liquid from the reaction vessel 
12 from spattering into the receiving flask. Vapors (which contain DMD and 
acetone) from the reaction vessel are carried through the glass wool 52 
with the aid of the helium carrier gas. Those vapors enter Y-tube 54, 
which is connected to condensation unit 56. The interior chamber 58 of 
condensation unit 56 contains a very cold mixture such as dry ice and 
acetone. As the vapor which contains DMD contacts the cold surfaces in 
condensation unit 56, it condenses. The condensate collects in the main 
receiving flask 60, via Y-tube 54. The condensate chills the Y-tube 54 and 
the receiving flask 60, causing some of the vapors to condense directly 
into the receiving flask. The receiving flask is also chilled directly, by 
means such as dry ice-acetone bath 62. 
Any vapors which are still in gaseous form after they pass through the 
condensation unit 56 can be collected via tube 70 in one or more cold 
traps 72 if desired. The applicants have found that a single trap 
containing dry ice and acetone is sufficient to collect the large majority 
of any remaining DMD. In industrial processes, it may be advisable to 
provide additional cold traps to ensure complete removal of any DMD. 
The DMD/acetone mixture collected in receiving flask 60 and in any cold 
traps can be stored in a conventional freezer (at 0.degree. C. or slightly 
colder temperatures) for up to about seven days with little or no 
degradation. If storage for more than a few days is required, the 
concentration of the DMD should be assayed shortly before it is used. 
The concentration of DMD in acetone solution can be assayed by various 
methods, In the work described in the Examples, the DMD concentrations 
were determined by the phenyl methyl sulfide method (Murray et al 1985). 
Other methods include a triphenylphosphine method (Murray et al 1985), UV 
spectroscopy (absorbance at 331-335 nm), and iodometric titration. 
Reaction of an exactly balanced stoichiometric amount of dioxirane with a 
selected secondary amine leads, after solvent removal, to the solid 
hydroxylamine. In most cases, the oxidation reaction is highly selective. 
For example, 1,4-dihydroxy-2,2,6,6-tetramethyl piperidine was prepared in 
high yield with no oxidation of the secondary alcohol group. In some 
cases, dioxirane oxidizes secondary alcohols to the corresponding ketone 
(Murray et al 1986). Apparently, the rate difference is heavily in favor 
of amine oxidation in the piperidine reaction. The same is believed likely 
to apply with regard to other compounds having both secondary amine and 
secondary alcohol groups. 
After the conversion of a secondary amine to a hydroxylamine is completed, 
using equimolar quantities of DMD and a secondary amine, the resulting 
hydroxylamine can be converted into a nitroxide or nitrone via a second 
reaction if an additional quantity of DMD is added. In most cases, the DMD 
reaction highly favors the secondary amine group rather than the 
hydroxylamine group. This normally leads to high yields of relatively pure 
hydroxylamines, as indicated in Tables 1 and 2, with little or no 
nitroxide present. However, when certain types of secondary amines are 
reacted with equimolar DMD, competing reactions can form small but 
significant quantities of nitroxides and/or nitrones. For example, 
N-phenyl-N-benzylamine is oxidized to a reaction mixture containing a 
majority of the hydroxylamine mixed with smaller quantities of nitroxides, 
nitrones, and unreacted amine. Such mixtures can be purified, if the 
hydroxylamine is the desired product. 
It should also be noted that the oxidation reactions described in the 
Examples have been performed on a variety of secondary amine compounds 
which have relatively reactive groups that were not altered by the 
dimethyldioxirane. Example 1 shows that a secondary alcohol group was left 
undisturbed by DMD oxidation. Example 2 shows that an aromatic ring was 
not altered or substituted. Examples 3 and 4 show that bicyclic groups 
with spiro configurations (i.e., the adjoining rings share a single carbon 
atom) were undisturbed, and that heterocyclic rings containing oxygen 
atoms were undisturbed. Example 5 shows that a complex polycyclic molecule 
(which functions as a precursor to several important cholesterol 
derivatives) was unaltered. Example 7 shows that (1) an unsaturated ring 
having a double bond was undisturbed, and (2) a relatively reactive 
carboxamide group was undisturbed. Example 8 shows that a nitro group was 
not disturbed. 
In addition, Murray et al 1988 indicates that several types of nitroxides 
were synthesized by reacting secondary amines with 2.times. molar 
quantities of DMD. Since those nitroxides were formed in a set of two 
reactions (i.e., conversion of the amine into a hydroxylamine, and 
conversion of the hydroxylamine into the nitroxide, all in a single 
vessel), it is clear that the potentially competing reactive groups 
contained on the secondary amines mentioned in that paper were also 
undisturbed by the DMD oxidation reaction. Those potentially reactive 
groups included a carboxylic acid group, a ketone, an oxime, an 
unsaturated ring with double-bonded carbons, and a group with 
triple-bonded carbons. 
Thus, this reaction has been shown to be highly selective for secondary 
amine groups, despite the presence of various types of potentially 
competing reactive groups.