Download PDF
Synthesis 2013; 45(3): 326-329
DOI: 10.1055/s-0032-1317861
practical synthetic procedures
© Georg Thieme Verlag Stuttgart · New York

A Revised Preparation of (4-Acetamido-2,2,6,6-tetramethylpiperidin-1-yl)oxyl and 4-Acetamido-2,2,6,6-tetramethyl-1-oxopiperidinium Tetrafluoroborate: Reagents for Stoichiometric Oxidations of Alcohols

Leon J. Tilley
a   Shields Science Center, Stonehill College, Easton, MA 02357, USA   Fax: +1(508)5651469   Email: ltilley@stonehill.edu
,
James M. Bobbitt*
b   Department of Chemistry, University of Connecticut, Storrs CT 06269-3060, USA   Fax: +1(1860)4862981   Email: james.bobbit@uconn.edu
,
Stephanie A. Murray
a   Shields Science Center, Stonehill College, Easton, MA 02357, USA   Fax: +1(508)5651469   Email: ltilley@stonehill.edu
,
Casey E. Camire
a   Shields Science Center, Stonehill College, Easton, MA 02357, USA   Fax: +1(508)5651469   Email: ltilley@stonehill.edu
b   Department of Chemistry, University of Connecticut, Storrs CT 06269-3060, USA   Fax: +1(1860)4862981   Email: james.bobbit@uconn.edu
,
Nicholas A. Eddy
b   Department of Chemistry, University of Connecticut, Storrs CT 06269-3060, USA   Fax: +1(1860)4862981   Email: james.bobbit@uconn.edu
› Author Affiliations
Further Information

Publication History

Received: 01 August 2012

Accepted after revision: 20 November 2012

Publication Date:
21 December 2012 (online)

 
 PDF Download Permissions and Reprints All articles of this category


Abstract

Revised preparations of (4-acetamido-2,2,6,6-tetramethylpiperidin-1-yl)oxyl and the corresponding oxoammonium salt, 4-acetamido-2,2,6,6-tetramethyl-1-oxoammonium tetrafluoroborate are presented together with some of the important properties of these two oxidizing­ reagents.


#

Key words

oxidations - catalysis - green chemistry - alcohols - aldehydes - ketones
Zoom Image
Scheme 1

This Practical Synthetic Procedure describes the revised preparation of the oxidizing agents (4-acetamido-2,2,6,6-tetramethylpiperidin-1-yl)oxyl (4) and 4-acetamido-2,2,6,6-tetramethyl-1-oxopiperidinium tetrafluoroborate (6) from 2,2,6,6-tetramethylpiperidin-4-amine (1) as shown in Scheme [1].

Highly selective and convenient oxidations of alcohols and certain other compounds can be easily carried out by using an oxoammonium ion such as 7 (Scheme [2]). This ion can be prepared via a nitroxide such as 8 or 4, or via salts of an oxoammonium ion such as 9 or 10 with various anions. These reactions have been extensively reviewed.[1] [2] [3] [4]

Catalytic oxidations can be carried out by using a nitroxide catalyst in the presence of a secondary oxidant such as aqueous sodium hypochlorite (bleach) or (bisacetoxyiodo)benzene [BAIB; diacetyl(phenyl)-λ3-iodane] (Scheme [2], equation 1).[ 1 ] Such catalytic oxidations are well represented in the literature because the reagents are inexpensive and effective. However, stoichiometric oxidations can be carried out by using the salts of the actual oxoammonium ions with a variety of counteranions.[ 5 ] The most common procedure involves oxidation in a mixture of dichloromethane and silica gel (Scheme [2], equation 2).[ 6 ] In the original paper,[ 6 ] the oxidations were carried out with the oxoammonium perchlorate 10·ClO4. This was later found to be unsafe,[ 7 ] and was replaced with the corresponding tetrafluoroborate 6, which, fortunately, had been prepared at the same time.

Zoom Image
Scheme 2 Oxoammonium chemistry

Reactions in the presence of pyridine bases can yield either aldehydes (with 2,6-dimethylpyridine)[8] [9] or dimeric esters (with pyridine) (Scheme [2], equation 3).[ 10 ] Stoichiometric oxidations can also be carried out by means of the Golubev disproportionation reaction[ 11 ] of a nitroxide with 4-toluenesulfonic acid, which generates the oxoammonium 4-toluenesulfonate salt for oxidations, (Scheme [2], equation 4).[ 12 ] Recent papers on stoichiometric oxidations describe oxidations in water,[ 13 ] oxidations of primary alcohols to carboxylic acids (showing some remarkable examples of selectivity),[ 14 ] two reactions in which a double bond is introduced adjacent to a carbonyl group,[15] [16] a benzyl ether cleavage,[ 17 ] double-bond additions (to trisubstituted alkenes),[ 18 ] and some intriguing condensation reactions promoted by oxidation.[19] [20] [21] [22]

We have been especially attracted to the 4-acetamido reagents 4 and 6 for several reasons. Firstly, they can be easily and inexpensively prepared from the industrial chemical 2,2,6,6-tetramethylpiperidin-4-amine, and are therefore readily available.[ 23 ] Secondly, the nitroxide 4, when used as a catalyst, is much more stable and less volatile­ than (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) and it has been found to give superior results to TEMPO in at least two cases.[24] [25] The oxoammonium salt 6 is also much more stable than the corresponding oxoammonium salts derived from TEMPO.[ 26 ] Thirdly, we favor these compounds because their solubility properties are almost perfect for neutral oxidation reactions (Scheme [2], equation 2). The colors and the approximate solubilities of some of the 4-acetamido compounds in various solvents are listed in Table 1.

Table 1 Solubilities and Colors of 4-Acetamido Compounds

Solubility (g/100 mL)

Color

H2O

CH2Cl2

Et2O

Nitroxide 4

3 at 0 °C
3.5 at r.t.
>50 at 100 °C

soluble

0.28 at r.t.

orange

Oxidant 6

6 at 0 °C
8 at r.t.
>50 at 100 °C

0.1 at r.t.

insoluble

yellow

Reduced oxidant 5

soluble

0.02 at r.t.

insoluble

white

The reaction is colorimetric in that the salt 6 is bright yellow and its reduced form 5 is white. During an oxidation, the color changes from bright yellow to white. Finally, the oxidation is environmentally friendly, as no metals are involved. The solubilities of the nitroxide in water, diethyl ether, and dichloromethane permit the removal of the nitroxide from diethyl ether by extraction with water and the removal of the nitroxide from water by extraction with dichloromethane, although more than one extraction may be needed.

The oxidant 6 and its reduction product 5 have very low solubilities in dichloromethane, and they are also ionic. The low solubility of 6 means that a constant low concentration of oxidant is present during the reaction, which may lead to functional-group selectivity. In a dichloromethane oxidation mixture, optionally containing silica gel, 6 and 5 can be completely removed by simple filtration through a 3- to 5-mm-thick pad of silica gel. This gives a solution of pure product in an essentially quantitative manner. The product can be isolated by evaporation of the solvent, or the dichloromethane solution can be used in subsequent tandem reactions. The disproportion reaction with 4-toluenesulfonic acid is similar, in that the oxoammonium tosylate 11 precipitates and the reaction gives good yields; however, the products sometimes require further purification.[ 12 ]

We have previously published descriptions of several methods for the preparation of 4 and 6 (Scheme [1]).[6] [12] [27] [28] [29] These preparations are handicapped by the fact that the oxidizing agents, hydrogen peroxide and commercial bleach, although inexpensive, are available only as dilute solutions. Both the nitroxide 4 and the oxoammonium salt 6 have appreciable solubilities in water (Table 1), which reduce the yields. The previous preparations and our revised preparation are summarized in Scheme [1].

In the original preparations, the first step, acylation of 1 to give the acetate salt 2, was carried out in dry diethyl ether, and 2 was isolated as such; this is an expensive operation. Salt 2 was then basified in a separate step and oxidized to give the nitroxide 4, which was also isolated. The nitroxide was then disproportionated with aqueous commercial tetrafluoroboric acid to give 5 and 6 by the Golubev reaction,[ 11 ] and further oxidized by treatment with 0.5 equivalents of commercial bleach (6% aqueous sodium hypochlorite) to complete the preparation of 6.

In our revised procedure, 1 is acylated in ice water and converted, in a one-pot reaction, directly into 4, which can be isolated by filtration in 90–95% yield. In the last step (the conversion of 4 into 6), by using the common-ion effect and salting out with sodium tetrafluoroborate, 6 can obtained in 90–92% yield.

All of the reactions were carried out with distilled H2O. For the sake of convenience, each of the two procedures was performed with 0.5 moles of starting material; the reactions were not contiguous. The procedures can be scaled up to one or more moles with the appropriate equipment. Melting points were measured on a Kofler Hot-Stage apparatus.

2,2,6,6-Tetramethylpiperidin-4-amine was obtained in bulk (500 mL) from TCI America (Portland, OR). HBF4 and NaBF4 were obtained in bulk (2.5 kg) from Alfa-Aesar (Ward Hill, MA). Sodium tungstate, EDTA, and H2O2 were obtained from various supply houses. Bleach (Chlorox) was purchased fresh for each experiment from a local supermarket.

The costs of the chemicals used to prepare 4 and 6 were about $0.55 and $0.53 per gram, respectively. Procedures are available for recovering nitroxide from spent oxidant,[6] [12] [29] but in the case of small-scale reactions, this might not be worth the trouble.

The approximate solubilities in Table 1 were measured as follows. For Et2O and CH2Cl2, portions of solvent (100 mL) were stirred for one day with an excess of the solid solute. The solutions were filtered and the solvent was evaporated to dryness to determine the solubility. For H2O, the solvent (100 mL) was stirred with a known amount of solute for one day and then the mixture was filtered. The weight of residual solid was subtracted from the total original weight of solute to obtain the solubility.


#

(4-Acetamido-2,2,6,6-tetramethylpiperidin-1-yl)oxyl (4)

Amine 1 (78.1 g, 0.5 mol) was dissolved in H2O (100 mL) in a 2-L beaker (because some of the reactions generate large amounts of foam) equipped with a large magnetic stirring bar (at least 3-in long). The stirred mixture was cooled to 0 °C in an ice bath, and ice (400 g) was added to the mixture. Ac2O (61.2 g, 0.60 mol) was then added dropwise over about 0.5 h at such a rate that the temperature remained near 0 °C. The mixture was then allowed to warm to r.t. and stirred for 1 h. Solid Na2CO3 (74.2 g, 0.7 mol) or K2CO3 (96.7 g, 0.7 mol) was then added slowly to the mixture. Some foaming occurred, and a white solid precipitate of amide 3 formed.

Catalysts Na2WO4 (9 g, 0.03 mol) and EDTA (9 g, 0.03 mol) were added to the mixture, followed by dropwise addition over 1 h of 30% H2O2 (223.0 g, 2.0 mol). The suspension turned yellow then orange, and a dense orange precipitate eventually formed. Because some heat was given off, the beaker was cooled by placed it in a pan of water at r.t. The mixture was stirred for 24–48 h or until foaming ceased. (This foaming is presumably caused by O2 from the H2O2.) The mixture was then vacuum filtered and the residue was dried over CaCl2 in vacuum at 50 °C; yield: 99–101 g, (93–95%); mp 145–147 °C (Lit.[ 6 ] 145–147 °C).

The product appears to be stable indefinitely and is resistant to air and moisture. It can be recrystallized from H2O (2.5 parts) with about a 15% loss, but this is not normally necessary.


#

4-Acetamido-2,2,6,6-tetramethyl-1-oxopiperidinium Tetrafluoroborate (6)

CAUTION: Tetrafluoroboric acid is extremely destructive to the skin, eyes, and respiratory tract.

Oxyl 4 (106.5 g, 0.5 mol) was slurried in H2O (200 mL) in a 2-L beaker containing a large stirring bar, and 50% aq HBF4 (100.0 g, 0.57 mol) was added dropwise over about 1 h. The orange slurry initially became brown–black and then turned yellow as a mixture of 10 and 6 formed by a disproportionation reaction. Commercial bleach [Chlorox (6% aq NaOCl); 308.0 g, 0.25 mol] was added dropwise over about 3 h to convert the mixture of 10 and 6 entirely into 6. NaBF4 (55.0 g, 0.5 mol) was added to salt out the product, and the mixture was stirred for 30 min, cooled in an ice bath for about 2 h, and vacuum filtered. The precipitate was washed with CH2Cl2 (200 mL) and air dried; yield: 136–139 g (91–93%); mp 190-195 °C (dec.; browned at ≥180 °C) (Lit.[ 29 ] 190–195 °C).

Anal. Calcd for C11H21N2O2BF4: C, 44.03; H, 4.04; N, 9.33. Found: C, 44.11; H, 6.91; N, 9.37.

Drying over CaCl2 under a vacuum at about 60 °C and 60–80 mm removed only about 0.2 g of additional H2O. The material appears to be stable indefinitely and is resistant to air and moisture.

This material is suitable for most oxidations. For special uses, it can be recrystallized but, because the salt reacts slowly with hot H2O,[ 30 ] the process must be carried out as quickly as possible. The salt (100 g) is added to rapidly boiling H2O (250 mL) and stirring with a stirrer bar. Dissolution is brought about as quickly as possible, and the mixture, which becomes black, is filtered through a hot coarse paper filter before NaBF4 (36.7 g, 1 equiv) is added. The solution is stirred briefly then cooled quickly in an ice bath. The bright, yellow solid is collected by filtration and air-dried; yield: 88.0 g; mp 193–195 °C (dec.). The loss is about 12%. The salt can be dried further under vacuum.


#
#

   Permissions and Reprints All articles of this category
Zoom Image
Scheme 1
Zoom Image
Scheme 2 Oxoammonium chemistry