Patent Application
20050006246
This invention is in the field of electrochemical atom transfer, particularly the introduction of a nitrogen atom into an organic molecule in an electrochemical process.
The reactions of organic compounds can be classified into two broad categories: carbon-carbon bond forming processes and reactions in which carbon atoms change their oxidation states (redox processes). The redox reactions in nature are accomplished by the enzyme molecules. These catalysts contain metal centers that carry out the requisite electron and/or atom transfer reactions. Over the years, remarkable progress has been achieved in design and applications of novel metal-based complexes. The metal center of a synthetic catalyst is surrounded by a small molecule ligand that often resembles and emulates the catalytic reaction site of an enzyme. One of the key roles of the ligand is to modulate reactivity at the metal center. This permits the reactivity of the metal ion in a given oxidation state to be adjusted to control the steric and electronic parameters of a given reaction. This strategy has been shown to adequately address the issues of regio-, chemo-, and stereoselectivity of a number of widely used synthetic transformations. The judicious choice of stoichiometric reductant or oxidant is required in order to render a given reaction catalytic in the metal reagent.
Aziridination of olefins is of particular current interest due to the enormous synthetic potential of aziridines.1 These nitrogen-containing heterocycles have 28 kcal/mol of strai2 and are amenable to ring-opening reactions with a wide range of nucleophiles. Such transformations lead to molecules with valuable 1,2-heteroatom relationships, commonly found in natural products and in pharmaceuticals.3 Olefin aziridination reactions are usually accomplished via metal-mediated transfer of a nitrene fragment to the olefin.4 The corresponding processes can produce a variety of by-products that stem from metal additives and from oxidants. To date, there are no examples of catalytic oxidation systems based on readily available oxidants that convert simple amines or amides into active nitrogen transfer species in the presence of olefins and leave no by-products.
A synthetically attractive route is the aziridination of olefins with N-aminophthalimide and lead tetraacetate as oxidant (eq. 1).5 However, its widespread application is hampered by the use of large amounts of Pb(OAc)4, known for its high toxicity.6
This invention provides an electrochemical process by which a new organic molecule is obtained through the formation of a nitrogen bond. An example is the formation of an aziridine by addition of the nitrogen across a double bond between two carbon atoms, in which two C—N bonds form. Another example is formation of a sulfoxime by addition of the nitrogen to the sulfur atom of a sulfoxide, in which a S═N bond forms. The results of the various addition reactions shown herein can be explained in terms of the formation of a nitrene intermediate formed under the electrochemical conditions of the invention.
In one aspect, the invention is an electrochemical process for the formation of a compound having formula I:
The process includes a step of contacting a compound having formula II and a compound having formula III with each other in an electrolytic cell under conditions of electrolysis sufficient to form the compound of formula I.
“A” shown in these formulae is selected from the group consisting of C, N and O, and
A is preferably a carbon atom, but it can be a nitrogen atom, or an oxygen atom.
The group from which each of R1, R2, R3, and R4 may be selected can be the group consisting of alkyl, alkenyl, alkynyl, aryl, phenyl, biphenyl, and substituted alkyl, alkenyl, alkynyl, aryl, wherein the substituents are selected from the group of alkyl, alkenyl, alkynyl, aryl, halide, ketone, aldehyde, alcohol, ether, ester, carboxylic acid, primary amino, secondary amino, tertiary amino, amide, nitrile, nitro, epoxide, imine, aziridine, sulfone, phosphone, and silane.
In another aspect, the group from which each of R1, R2, R3, and R4 may be selected is the group consisting of alkyl, alkenyl, alkynyl, aryl, and substituted alkyl, alkenyl, alkynyl, aryl, wherein the substituents are selected from the group of alkyl aryl, halide, ketone, aldehyde, alcohol, ether, ester, carboxylic acid, primary amino, secondary amino, tertiary amino, amide, nitro, epoxide, aziridine, sulfone, phosphone, and silane.
In a narrower aspect, the group from which each of R1, R2, R3, and R4 may be selected can the group consisting of alkyl and aryl, and substituted alkyl and aryl, wherein the substituents are selected from the group of alkyl, aryl, halide, ketone, aldehyde, alcohol, ether, ester, carboxylic acid, primary amino, secondary amino, tertiary amino, amide, nitro, epoxide, aziridine, sulfone, phosphone, and silane.
More particularly, the substituents can be selected from the group of halide, ketone, alcohol and ester.
In another aspect, “A” of starting compound II is a carbon atom, (i) if R3 and R4 are each hydrogen, then each of R1 and R2 is not hydrogen, or the double bond shown in formula II is conjugated with another olefinic double bond, (ii) if a first carbon atom of the double bond shown in formula II is in an α-position with respect to a carbonyl group of R1, then the second carbon atom of the double bond is not in an α-position with respect to a carbonyl group of R3, and (iii) if a first carbon atom of the double bond shown in formula II is in an α-position with respect to a carbonyl group of R2, then the second carbon atom of the double bond is not in an α-position with respect to carbonyl group of R4.
In another aspect of a process of the invention, II is selected from the group consisting of cyclohexene, cyclohex-2-enone, 2-methyl-pent-2-ene, 3-bromo-2-methyl-propene, trans-3-phenyl-acrylic acid methyl ester, cyclooctene, 2-methyl-buta-1,3-diene, trans-1,3-diphenylpropenone, trans-hex-4-en-3-one, trans-but-2-enedioic acid dimethyl ester, trans-3-phenyl-prop-2-en-1-ol, trans-4-phenyl-but-3-enoic acid methyl ester, 2-(acetoxy-phenyl-methyl)-acrylic acid methyl ester, 2-(hydroxy-phenyl-methyl)-acrylic acid methyl ester, trans-1,4-dichlorobutene, cis-1,4 dichlorobutene, 2-(phenylp-toluenesulfonamidomethyl)acrylic acid methyl ester and any derivative thereof obtained by substitution of a hydrogen of a C—H bond with an alkyl, phenyl, halide, ketone, aldehyde, alcohol, ether, ester, carboxylic acid, primary amino, secondary amino, tertiary amino, amide, nitro, epoxide, aziridine, sulfone, phosphone, and silane, wherein any such group can itself be substituted with a said group.
In a specific aspect, compound II is selected from the group consisting of cyclohexene, cyclohex-2-enone, 2-methyl-pent-2-ene, 3-bromo-2-methyl-propene, trans-3-phenyl-acrylic acid methyl ester, cyclooctene, 2-methyl-buta-1,3-diene, trans-1,3-diphenylpropenone, trans-hex en-3-one, trans-but-2-enedioic acid dimethyl ester, trans-3-phenyl-prop-2-en-1-ol, trans-4-phenyl-but-3-enoic acid methyl ester, 2-(acetoxy-phenyl-methyl)-acrylic acid methyl ester, 2-(hydroxy-phenyl-methyl)-acrylic acid methyl ester, trans-1,4-dichlorobutene, cis-1,4 dichlorobutene, and 2-(phenyl p-toluenesulfonamidomethyl)acrylic acid methyl ester.
In another aspect, the invention is process for the syn-addition of a nitrogen atom across a double bond.
The R5 group of compound III, can be selected from the specific group:
wherein each of R8, R9, R10, R11, R12 and R13 is an organic group.
Even more specifically, each of R8, R9, R10, R11, R12 and R13 can be selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, phenyl, biphenyl and substituted alkyl, alkenyl, alkynyl, aryl, phenyl and biphenyl wherein the substituents are selected from the group of alkyl, alkenyl, alknyl, aryl, halide, ketone, aldehyde, alcohol, ether, ester, carboxylic acid, primary amino, secondary amino, tertiary amino, amide, nitrile, nitro, epoxide, imine, aziridine, sulfone, phosphone, and silane.
In a narrower aspect of the invention, each of R8, R9, R10, R11, R12 and R13 can be selected from the group consisting of alkyl, aryl, phenyl and substituted alkyl, aryl and phenyl, wherein the substituents are selected from the group of alkyl, aryl, phenyl, halide, ketone, aldehyde, alcohol, ether, ester, carboxylic acid, primary amino, secondary amino, tertiary amino, amide, nitro, epoxide, aziridine, sulfone, phosphone, and silane Each of R8, R9, R10, R11, R12 and R13 preferably includes up to 20 carbon atoms, more preferably up to 18 carbon atoms, more preferably up to 16 carbon atoms, more preferably up to 14 carbon atoms, or up to 12 carbon atoms, or up to 10 carbon atoms, or up to 8 carbon atoms, or up to 6 carbon atoms.
Each of the substituents of the substituted groups from which R8, R9, R10, R1 1, R12 and R13 can be selected is preferably selected from the group consisting of halide, ketone, alcohol and ester, and more preferably from halide, alcohol and ester.
In a specific aspect of the invention, the compound having formula III is N-aminophthalimide. Any of the four C—H bonds of this molecule can be replaced with substituents that would not destroy the primary amino group of this compound to be electrochemically oxidized, i.e., alkyl, aryl, halide, alkyl halide, etc.
In another aspect of the invention, the compound having formula Im has a lower oxidation potential than that of a compound having formula II. It is also preferred that the compound having formula III is oxidized at a faster rate than a compound having formula II under the conditions of electrolysis of the invention.
The solvent the electrolytic cell can be a polar non-protic solvent, and particularly wherein the solvent can be selected from the group consisting of dichloromethane, acetonitrile, N,N-dimethylformamide, tetrahydrofuran, nitromethane, chloroform, propylene carbonate, and mixtures thereof, or other solvent suitable for conducting an electrochemical process of the invention.
In another aspect, the invention is an electrochemical process for the formation of a compound having formula IV,
In this aspect, the process includes contacting a compound having formula V and a compound having formula III with each other in an electrolytic cell under conditions of electrolysis sufficient to form the compound of formula IV.
In the indicated formulae,
The “B” is most preferably a sulfur atom, but it can be a phosphorus atom, a selenium atom, or a tellurium atom.
The group of organic groups from which each of R14, and R15 may be selected can be the group of alkyl, alkenyl, alkynyl, aryl, phenyl, biphenyl, and substituted alkyl, alkenyl, alkynyl, aryl, phenyl and biphenyl wherein the substituents are selected from the group of alkyl, alkenyl, alkynyl, aryl, halide, ketone, aldehyde, alcohol, ether, ester, carboxylic acid, primary amino, secondary amino, tertiary amino, amide, nitrile, nitro, epoxide, imine, aziridine, sulfone, phosphone, and silane.
More particularly, the group from which each of R14, and R15 may be selected can be the group consisting of alkyl, alkenyl, alkynyl, aryl, and substituted alkyl, alkenyl, alkynyl, aryl, wherein the substituents are selected from the group of alkyl, aryl, halide, ketone, aldehyde, alcohol, ether, ester, carboxylic acid, primary amino, secondary amino, tertiary amino, amide; nitro, epoxide, aziridine, sulfone, phosphone, and silane.
Even more particularly, the group from which each of R14, and R15 may be selected is the group consisting of alkyl and aryl, and substituted alkyl and aryl, wherein the substituents are selected from the group of alkyl, aryl, halide, ketone, aldehyde, alcohol, ether, ester, carboxylic acid, primary amino, secondary amino, tertiary amino, amide, nitro, epoxide, aziridine, sulfone, phosphone, and silane. More particularly, wherein the substituents are selected from the group of halide, ketone, alcohol and ester, and more particularly, halide, alcohol and ester.
The invention includes a process wherein compound V is selected from the group consisting of compounds VIII to XV:
and any derivative of any of compounds VII to XV obtained by substitution of a hydrogen of a C—H bond with an alkyl, phenyl, halide, ketone, aldehyde, alcohol, ether, ester, carboxylic acid, primary amino, secondary amino, tertiary amino, amide, nitro, epoxide, aziridine, sulfone, phosphone, and silane, wherein any said group can itself include such a substituent.
More specifically, compound V can be selected from any of compounds VIII to XV.
R5 can be selected as described above, for reaction of compound V and III.
In a particular embodiment, the compound having formula III has a lower oxidation potential than that of a compound having formula II. Further, the compound having formula III is oxidized at a faster rate than a compound having formula II under the conditions of electrolysis.
In another aspect, the invention is an electrochemical process for the formation of a compound having formula VI:
Here, the process involves contacting a compound having formula VII and a compound having formula III with each other in an electrolytic cell under conditions of electrolysis sufficient to form the compound of formula VI.
In this aspect of the invention,
In one aspect of this process of the invention, the group from which each of R16, and R17 may be selected can be the group consisting of alkyl, alkenyl, alkynyl, aryl, phenyl, biphenyl, etc., and substituted alkyl, alkenyl, alkynyl, aryl, phenyl, biphenyl wherein the substituents are selected from the group of alkyl, alkenyl, alkynyl, aryl, halide, ketone, aldehyde, alcohol, ether, ester, carboxylic acid, primary amino, secondary amino, tertiary amino, amide, nitrile, nitro, epoxide, imine, aziridine, sulfone, phosphone, and silane.
The group from which each of R16, and R17 may be selected, in a narrower aspect of the invention, is the group consisting of alkyl, alkenyl, alkynyl, aryl, and substituted alkyl, alkenyl, alkynyl, aryl, wherein the substituents are selected from the group of alkyl, aryl, halide, ketone, aldehyde, alcohol ether, ester, carboxylic acid, primary amino, secondary amino, tertiary amino, amide, nitro, epoxide, aziridine, sulfone, phosphone, and silane.
The group from which each of R16, and R17 may be selected can also be the group consisting of alkyl and aryl, and substituted alkyl and aryl, wherein the substituents are selected from the group of alkyl, aryl, halide, ketone, aldehyde, alcohol, ether, ester, carboxylic acid, primary amino, secondary amino, tertiary amino, amide, nitro, epoxide, aziridine, sulfone, phosphone, and silane.
More preferably, the substituents are selected from the group of halide, ketone, alcohol and ester.
Again, wherein R5 of compound III can be selected as previously described.
The compound having formula III preferably has a lower oxidation potential than that of a compound having formula II, and preferably is oxidized at a faster rate than a compound having formula II under the conditions of electrolysis.
In one general aspect, the invention involves including a carboxylate anion in the anodic cell in which the hydrazine compound II is oxidized. Preferably, the cell is substantially free, or even completely free, of a toxic metal catalyst. Toxic metal catalysts that are to avoided include of lead cadmium, cerium, cobalt, chromium, copper, ion, mercury, iridium, manganese, molybdenum, nickel, osmium, palladium, rhenium, rhodium, ruthenium, antimony, thallium, tin and vanadium.
The anodic electrode is preferably a platinum electrode.
In a preferred aspect, the acid form of the carboxylate has a first pKa, and the anolyte solution further includes an acid having a second pKa wherein the second pKa exceeds the first pKa.
Preferably, the carboxylate and the acid having the second p& are solubilized in the solution and the carboxylate is provided in solution in a stoichiometric amount equal to at least half that of the hydrazine derivative, but more preferably to at least 60% that of the hydrazine derivative, or at least 70% that of the hydrazine derivative, or 80% that of the hydrazine derivative, or 90% that of the hydrazine derivative, or the carboxylate can be present in a stoichiometric amount about equal to that of the hydrazine derivative, or it could be said, in an amount at least as great as that of the hydrazine derivative.
Usually, the acid form of the carboxylate has the formula RCO2H wherein R is an organic group. According to a preferred aspect, the acid for of the carboxylate has the formula RCO2H wherein R is an alkyl group or a haloalkyl group.
The first pKa is preferably in the range of about −2 to about +7, more preferably in the range of about −1 to about +6, more preferably in the range of about 0 to about +5. The first pKa can be about 0.3 first pKa, or it can be about 2.8, or the first pKa can be about 4.8. The carboxylate can be one or more of acetate, trifluoroacetate, and monochloroacetate.
The acid is preferably an ammonium acid and the second pKa preferably exceeds the first pKa by at least 2. The ammonium acid typically has the wherein each of R1, R2 and R3 is an organic group or hydrogen. Commonly, each of R1, R2 and R3 of the ammonium acid is an alkyl group (e.g., methyl, ethyl, propyl, butyl and pentyl) or hydrogen. In a specifically disclosed aspect of the invention, the acid having the second pKa is triethylammonium.
In another aspect, the anolyte solution includes a counterion to the carboxylate, the counterion having the formula R1R2R3 R4 N+ wherein each of R1, R2, R3, and R4 is an organic group selected from the group described in connection with R1, R2 and R3 of R1R2R3NH+.
The contacting step is preferably carried out in an anodic half cell divided from and operatively linked to a cathodic half cell. Preferably, the half cells are linked by an ion permselective diaphragm. The diaphragm is preferably made up of a synthetic polymer having anions affixed (usually covalently bonded) thereto. A preferred anion is perfluorosulfonate. A commercially available diaphragm suitable for many aspects of the invention is that sold under the name Nafion.
In one aspect of the invention, compound II, V, or VII, as the case may be, has a more positive potential than the voltage at which the contacting step is conducted.
Compound III preferably has first and second peak potentials, each of which potentials is between about 0 and 3 volts against Ag/AgCl, more preferably between about 1 and 2 volts.
Preferably, the mole ratio of the compound having formula III to the compound having formula II, V, or VII, as the case may be, is from about 1:1 to about 1000:1; more preferably between 500:1 and 1:1; more preferably between about 100: and 1:1; more preferably between about 25:1 and 1:1; more preferably between about 10:1 and 1:1; more preferably between about 5:1 and 1:1, more preferably between about 2:1 and 1:1.
The process can be carried out such that the electric potential applied during the contacting step is applied for a period between about 1 minute and 10 hours.
In another aspect the invention is a process of addition of a nitrogen across a multiple bond of an organic molecule wherein a first atom of the multiple bond is a carbon atom, and the second atom is selected from the group of carbon, oxygen and nitrogen, the improvement comprising electrochemically generating the nitrogen for the addition from a primary hydrazine derivative in the presence of a carboxylate anion. It is preferred here that the nitrogen is generated from a compound having the structure indicated by formula III, as defined above and that the organic molecule has the structure indicated by formula I formula VII.
Another process of the invention is addition of a nitrogen to a heteroatom of an organic molecule wherein the heteroatom forms a double bond with an oxygen atom and is a P, S, Se or Te atom, the improvement comprising electrochemically generating the nitrogen for the addition from a primary hydrazine derivative in the presence of a carboxylate anion. Again, the nitrogen is preferably generated from a compound having the structure indicated by formula III, as defined above and the organic molecule has the structure indicated by formula V.
Another aspect of the invention is a process for electrochemically generating a nitrene. The process includes exposing a hydrazine derivative contained in an anolyte solution of an electroytic cell to the anode of the cell in the presence of a carboxylate ion, wherein one of the nitrogens of the hydrazine group is a primary amino group.
Preferably, the anolyte solution is substantially free of a metal catalyst, particularly a toxic metal catalyst.
Preferably, the anode a platinum electrode.
Preferably, an acid form of the carboxylate has a first pKa, and the anolyte solution further comprises an acid having a second pKa wherein the second pKa exceeds the first pKa, and the carboxylate and acid (or counterion to the carboxylate) are selected as described above.
Preferably, the carboxylate and the acid having the second pKa are solubilized in the solution and the carboxylate is provided in solution in a stoichiometric amount equal to at least half that of the hydrazine derivative, but more preferably to at least 60% that of the hydrazine derivative, or at least 70% that of the hydrazine derivative, or 80% that of the hydrazine derivative, or 90% that of the hydrazine derivative, or the carboxylate can be present in a stoichiometric amount about equal to that of the hydrazine derivative, or it could be said, in an amount at least as great as that of the hydrazine derivative.
In this process for generating a nitrene, the hydrazine derivative can be a molecule having the structure indicated as formula III as described above, and the anolyte solution can be a solvent as described above.
In another aspect, the invention is an apparatus for electrochemical generation of a nitrene. The apparatus includes an anodic half cell operatively linked to a cathodic half cell, and an anolyte solution comprising a carboxylate anion and a primary hydrazine derivative.
Preferably, the half cells are linked by an ion permselective diaphragm. A preferred diaphragm is a synthetic polymer having anions affixed thereto, as by covalent bonding, and the anions can include perfluorosulfonate groups. A commercially available diaphragm suitable for use according to many processes of the invention is a Nafion membrane.
The hydrazine of the apparatus includes any of those having formula III, as described above.
Preferably, the anolyte solution is substantially free of a metal catalyst
Preferably, the anode of the apparatus is a platinum electrode.
Preferably, the an acid form of the carboxylate of the apparatus has a first pKa, and the anolyte solution includes an acid having a second pKa wherein the second pKa exceeds the first pKa. The carboxylate and counterion included in the apparatus can be selected and included in the apparatus as described above.
An apparatus of the invention can be used for nitrene generation, an aziridination, sulfoximation, or other nitrogen addition to a suitable organic substrate.
Another aspect of the invention is a process for screening an olefin for electrochemical aziridination of an olefin with a hydrazine derivative, the process comprising the steps of:
In another aspect, the invention is a process for screening an olefin for electrochemical aziridination of an olefin with a hydrazine derivative, the process comprising the steps of:
Preferably, the hydrazine derivative has first and second peak potentials, each of which potentials is between about 0 and 3 volts against Ag/AgCl, more preferably between about 1 and 2 volts.
Reference is made to the attached drawings, in which:
General Information
Cyclohexene, 2-cyclohexen-1-one, 2-methyl-2-pentene, 3-bromo-2-methyl-1-propene, methyl trans-cinnamate, cyclooctene, isoprene, trans-chalcone, 4-hexen-3-one, dimethyl fumarate, dimethyl maleate, cinnamyl alcohol, hydrazine monohydrate, phthalimide, cis- and trans-1,2-dichlorobutene, methyl p-tolyl sulfoxide, phenyl sulfoxide, phenyl vinyl sulfoxide, tetramethylene sulfoxide, benzyl phenyl sulfide, thiophenol, acrylonitrile, tetrabutylammonium hydroxide, 3-chloroperoxybenzoic acid (mCPBA), anisole, sodium benzenesulfinate, thionyl chloride, benzoylchloride, and triethylamine were purchased from Aldrich Chemical Company. DMSO was purchased from BDH Inc., Canada. Anhydrous aluminum chloride was purchased from Anachemia Canada Inc. Column chromatography was carried out using 230-400 mesh silica gel. 1H NMR spectra were referenced to residual CHCl3 (δ 7.26 ppm) and 13C spectra were referenced to CDCl3 (δ 77.2 ppm). Cyclic voltammetry characterization was conducted on a BAS CV-50W Voltammetric Analyzer (Bioanalytical Systems, Inc.) equipped with a BAS C3 three-electrode cell stand. A three-compartment (anodic: 2.0 cm dia.×10 cm; cathodic: 2.0 cm dia.×10 cm; reference: 1.0 cm dia×7 cm) divided cell with glass frit (medium pore size) separators was used for electrochemical aziridination of olefins and imination of sulfoxides. HPLC analysis was performed on a Hewlett Packard Series 1100 HPLC system with a Daicel Chiralcel AS column.
N-aminophthalimide7: Hydrazine monohydrate (4.4 g) in 95% ethanol (80 mL) was treated with powdered phthalimide (12 g) and the mixture was stirred at room temperature for 2 min. The resulting spongy mass was quickly heated and refluxed for 3 min. while ammonia was evolved. Cold water (250 mL) was added at once and N-aminophthalimide crystallized during an hour. Recrystallization from 95% ethanol gave white needles (5.6 g, 43%, Mp 223-224° C.).
Electrochemical Aziridination of Cyclohexene
The anodic compartment was charged with 82 mg (1.0 mmol) cyclohexene, 210 mg (1.3 mmol) N-aminophthalimide, 60 mg (1.0 mmol) acetic acid (glacial), 101 mg (1.0 mmol) triethylamine, and 20 mL acetonitrile. Portions of 0.05 M AcOH in MeCN were added to the cathodic (20 mL) and reference (4 mL) compartments. Platinum foils (2.5×2.5 cm, 99.99%) were used as working and auxiliary electrodes. Silver wire (1.5 mm dia., 99.99%) was used as a pseudo-reference electrode. The electrolysis was performed at +1.80 V (with an AMEL potentiostat, Model 2049) at ambient temperature and was stopped when the cell current dropped to less than 5% of its original value. The contents of anodic compartment were collected and concentrated in vacuo. The residue was washed with water and extracted with dichloromethane (3×5 mL). The organic phases were combined, dried over MgSO4, concentrated, charged onto a silica gel column, and eluted using EtOAc/hexane (1:3) which afforded 7-phthalimido-7-azabicyclo[4.1.0]heptane (1) as a yellow solid (223 mg, 85%).
Electrochemical aziridination of each of the olefin substrates listed in Table 1 was carried out, and products isolated, under similar conditions, except that for the aziridination of isoprene, which was carried out at 0° C. to avoid evaporation of isoprene.
The compounds were characterized as indicated below.
7-Phthalimido-7-azabicyclo[4.1.0]heptane (1): 1H NMR (CDCl3) δ: 7.24-7.75 (m, 4H), 2.72-2.75 (m, 2H), 2.20-2.30 (m, 2H), 1.90-2.10 (m, 2H), 1.20-1.50 (m, 4H). Mp 132-133° C. (lit.8 133-136° C.).
7-Phthalimido-7-aiabicyclo[4.1.0]heptan-2-one (2): 1H NMR (CDCl3) δ: 7.60-7.90 (m, 4H), 3.42-3.46 (m, 1H), 3.07 (d, 1H, J=7.2 Hz), 2.49-2.56 (m, 2H), 1.60-2.15 (m, 4H). 13C NMR (CDCl3) δ: 202.91, 164.31, 134.00, 129.90, 122.98, 48.86, 45.97, 36.77, 21.78, 18.03. HRMS 256.0841 (Calc. 256.0848 for C14H12N2O3). Mp 75-77° C.
1-Phthalimido-2-ethyl-3,3-dimethylaziridine (3): 1H NMR (CDCl3) δ: 7.64-7.76 (m, 4H), 2.74 (t, 2H, J=7.0 Hz), 1.78-1.90 (m, 1H), 1.48-1.61 (m, 1H), 1.39 (s, 3H), 1.27 (s, 3H), 1.14 (t, 1H, J=7.3 Hz). 13C NMR (CDCl3) δ: 166.35, 134.01, 130.90, 122.95, 54.38, 47.92, 22.10, 21.07, 19.22, 11.50. HRMS 244.1209 (Calc. 244.1212 for C14H16N2O2).
1-Phthalimido-2-bromomethyl-2-methylaziridine (4): 1H NMR (CDCl3) δ: 7.65-7.85 (m, 4H), 3.77 (dd, 0.78H, J=10.5, 1.0 Hz), 3.73 (dd, 0.22H, J=10.5, 1.8 Hz), 3.27 (d, 0.78H, J=10.5 Hz), 3.17 (d, 0.22H, J=10.5 Hz), 2.93 (dd, 0.78H, J=1.0, 3.0 Hz), 2.89 (d, 0.22H, J=2.7 Hz), 2.64 (m, 0.22H), 2.61 (d, 0.78H, J=3.0 Hz). 13C NMR (CDCl3) δ: 165.95, 134.45, 134.36, 130.62, 123.39, 123.31, 46.25, 43.20, 39.24, 15.97. HRMS 294.0018 (Calc. 294.0004 for C12H11BrN2O2). Mp 81-82° C.
1-Phthalimido-3-phenyl-2-aziridine carboxylic acid methyl ester (5): 1H NMR (CDCl3) δ: 7.60-7.80 (m, 4H), 7.30-7.50 (m, 5H), 4.37 (d, 1H, J=5.1 Hz), 3.72 (s, 3H), 3.51 (d, 1H, J=5.1 Hz). 13C NMR (CDCl3) δ: 166.73, 164.65, 134.48, 134.08, 130.19, 128.66, 127.25, 123.13, 52.96, 49.66, 45.96. Mp 141-142° C. (lit.9 144° C.).
9-Phthalimido-9-azabicyclo[6.1.0]nonane (6): 1H NMR (CDCl3) δ: 7.65-7.80 (m, 4H), 2.52-2.56 (m, 4H), 1.20-1.80 (m, 10H). 13C NMR (CDCl3) δ: 165.19, 133.96, 130.60, 122.91, 48.05, 26.54, 26.47, 25.45. Mp 88-89° C. (lit.10 89° C.).
1-Phthailmido-2-isopropenylaziridine (7)11: 1H NMR (CDCl3) δ: 7.60-7.80 (m, 4H), 5.13 (m, 1H), 5.05 (quintet, 1H, J=1.5 Hz), 3.04 (t, 1H, J=6.9 Hz), 2.57-2.62 (m, 2H), 1.84 (t, 3H, J=1.5 Hz). 13C NMR (CDCl3) 6:165.01, 140.49, 134.08, 130.35, 123.03, 114.83, 46.72, 37.69, 19.26.
1-Phthalimido-2-benzoyl-3-phenylaziridine (8): 1H NMR (CDCl3) δ: 8.05-8.15 (m, 2H), 7.30-7.80 (m, 12H), 4.69 (d, 1H, J=4.8 Hz), 4.39 (d, 1H, J=4.8 Hz). 13C NMR (CDCl3) δ: 190.39, 164.50, 137.25, 135.15, 133.95, 133.59, 130.19, 128.74, 128.73, 128.66, 128.57, 127.20, 123.10, 50.73, 48.77. Mp 121-123° C. (lit.12 124° C.).
1-Phthalimido-2-methyl-3-propionylaziridine (9): 1H NMR (CDCl3) δ: 7.55-7.80 (m, 4H), 3.38 (quintet, 0.83H, J=5.7 Hz), 3.31 (d, 0.17H, J=5.4 Hz), 3.22 (d, 0.85H, J=5.1 Hz), 2.95-3.12 (m, 1H), 2.63-2.76 (m, 1.17H), 1.50 (d, 0.83H, J=5.7 Hz), 1.42 (d, 0.17H, J=5.4 Hz), 1.13 (t, 0.17H, J=7.2 Hz), 1.04 (t, 0.83H, J=7.2 Hz). 13C NMR (CDCl3) δ: 202.33, 164.91, 134.36, 133.98, 130.35, 123.32, 123.07, 49.88, 45.22, 37.94, 16.81, 7.81. HRMS 258.0994 (Calc. 258.1004 for C14H14N2O3). Mp 102-103.5° C.
trans-1-Phthalimido-2,3-aziridine dicarboxylic acid dimethyl ester (10)13: 1H NMR (CDCl3) δ: 7.65-7.80 (m, 4H), 3.97 (d, 1H, J=4.8 Hz), 3.87 (s, 3H), 3.75 (s, 3H), 3.61 (d, 1H, J=4.8 Hz). 13C NMR (CDCl3) δ: 166.60, 165.34, 164.10, 134.34, 130.05, 123.49, 53.56, 53.41, 44.94, 42.94. Mp 149-150° C. X-ray data for 10 (recrystallized from chloroform/hexane): C14H12N2O6, MW=304.26, pale yellow prismatic crystal, crystal size 0.35×0.34×0.25 mm3, orthorhombic, space group Pbca, a=7.3819(2) A, b=16.9618(7) Å, c=22.3703(8) Å, V=2800.99(17) Å3, Z=8, dcalc=1.443 g/cm3, F(000)=1264, μ=0.115 mm−1, T=150(1) K, 13499 reflections collected, 2447 independent reflections, R=0.0435, Rw=0.1021, GOF on F2=1.020.
1-Phthalimido-2-hydroxymethyl-3-phenylaziridine (11): 1H NMR (CDCl3) δ: 7.15-7.45 (m, 5H), 7.65-7.80 (m, 4H), 4.15-4.35 (m, 1H), 4.02-4.10 (m, 0.36H), 3.80-3.90 (m, 0.64H), 3.40-3.60 (m, 1.36H), 3.18-3.22 (m, 0.64H), 2.57 (t, 0.36H, J=6.0 Hz), 2.69 (bs, 0.64H). 13C NMR (CDCl3) δ: 166.63, 135.82, 134.59, 134.04, 130.49, 129.51, 128.85, 128.67, 128.29, 128.25, 127.30, 123.51, 123.03, 62.31, 59.30, 52.42, 48.96, 46.65, 46.29. HRMS 294.1000 (Calc. 294.1004 for Cl7H14N2O3). Mp 141-142° C.
1-Phthalimido-2-phenyl-3-aziridine acetic acid methyl ester (12): 1H NMR (CDCl3) δ: 7.20-7.80 (m, 9H), 4.34 (dd, 0.47H, J=1.6, 5.6 Hz), 3.89 (d, 0.53H, J=5.6 Hz), 3.76 (s, 1.41H), 3;71 (s, 1.59H), 3.66 (d, 0.47H, J=1.6 Hz), 3.05-3.23 (m, 1.53H), 2.50-2.70 (m, 1H). 13C NMR (CDCl3) δ: 170.85, 170.73, 166.13, 136.35, 135.26, 134.44, 134.03, 130.99, 130.60, 129.71, 128.87, 128.63, 128.27, 128.17, 127.41, 124.58, 123.32, 122.98, 52.32, 52.17, 51.56, 48.40, 45.53, 41.05, 37.49, 33.36. HRMS 336.1097 (Calc. 336.1110 for Cl9H16N2O4). Mp 113-115° C.
1-Phthalimido-2-phenylacetoxymethyl-2-aziridine carboxylic acid methyl ester (13, mixture of two diastereomers): 1H NMR (CDCl3) δ: 7.55-7.75 (m, 4H), 7.20-7.45 (m, 5H), 3.66 (s, 1H), 3.54-3.56 (m, 2.33H), 3.48 (d, 0.67H, J=1.8 Hz), 2.95 (d, 0.67H, J=1.8 Hz), 2.83 (d, 0.33H, J=2.1 Hz), 2.15 (s, 1H), 2.10 (s, 2H). 13C NMR (CDCl3) δ: 169.28, 169.19, 166.44, 166.18, 164.46, 164.31, 136.55, 135.42, 134.15, 134.00, 130.21, 130.09, 128.70, 128.36, 128.25, 128.20, 127.83, 127.65, 123.45, 123.02, 72.83, 70.80, 53.37, 53.16, 48.69, 39.57, 38.68, 21.15. HRMS 394.1151 (Calc. 394.1165 for C21H18N2O6).
1-Phthalimido-2-phenylhydroxymethyl-2-aziridine carboxylic acid methyl ester (14, mixture of two diastereomers): 1H NMR (CDCl3) δ: 7.60-7.80 (m, 4H), 7.20-7.45 (m, 5H), 5.70 (s, 0.82H), 5.16 (s, 0.181H), 3.80 (b, 1H), 3.64 (d, 0.181H, J=2.1 Hz), 3.61 (s, 2.46H), 3.58 (d, 0.82H, J=1.8 Hz), 3.55 (s, 0.541), 2.91 (d, 0.18H, J=2.1 Hz), 2.85 (d, 0.82H, J=1.8 Hz). 13C NMR (CDCl3) 8:167.01, 165.05, 139.24, 134.34, 130.21, 128.55, 128.51, 128.37, 127.94, 127.71, 126.81, 126.73, 123.69, 123.37, 73.37, 70.11, 53.26, 52.06, 50.98, 40.19. HRMS 352.1062 (Calc. 352.1059 for Cl9H16N2O5).
trans-1-Phthalimido-2,3-bis(chloromethyl)aziridine (15a): 1H NMR (CDCl3) δ: 7.60-7.80 (m, 4H), 4.08 (dd, 2H, J=6.0, 11.7 Hz), 3.54 (dd, 2H, J=8.1, 11.7 Hz), 3.20-3.25 (m, 2H). 13CNMR (CDCl3) δ: 164.75, 134.57, 130.22, 123.52, 48.05, 40.14.
cis-1-Phthalimido-2,3-bis(chloromethyl)aziridine (15b): 1H NMR (CDCl3) δ: 7.60-7.80 (m, 4H), 4.00-4.06 (m, 2H), 3.45-3.60 (m, 3H), 2.98 (dt, 1H, J=5.1, 7.5 Hz). 13C NMR (CDCl3) δ: 165.85, 134.62, 130.48, 123.56, 47.03, 46.48, 43.50, 40.67.
1-Phthalimido-2-phenyltosylaminomethyl-2-aziridine carboxylic acid methyl ester (16): 1H NMR (CDCl3) δ: 7.65-7.80 (m, 4H), 7.63 (d, 2H, J=12.5 Hz), 7.38 (d, 1H, J=8.2 Hz), 7.18 (bs, 5H), 7.13 (d, 2H, J=12.5 Hz), 5.49 (d, 1H, J=8.2 Hz), 3.50 (s, 3H), 3.48 (d, 1H, J=3.1 Hz), 2.35 (s, 3H), 2.12 (d, 1H, J=3.1 Hz). 13C NMR (CDCl3) δ: 166.82, 165.43, 142.58, 138.93, 136.34, 134.48, 130.14, 129.21, 128.37, 128.29, 128.11, 127.26, 123.56, 56.56, 53.44, 49.09, 41.91, 21.55. X-ray data for 16 (recrystallized from chloroform/hexane): C26H23N3O6S, MW=505.53, colorless prismatic crystal, crystal size 0.29×0.28×0.28 mm3, triclinic, space group P1, a=7.9575(1) Å, α87.6210(10)°, b=8.8478(1) Å, β=79.6990(10)°, c=17.3936(3) Å, γ=73.6590(10)°, V=1156.16(3) Å3, Z=2, dcalc=1.452 g/cm3, F(000)=528, μ=0.190 mm−1, T=150(1) K, 13257 reflections collected, 5282 independent reflections, R=0.0448, Rw=0.0949, GOF on F2=1.045.
Sulfoxide Syntheses
2-Cyanoethyl phenyl sulfoxide: A modified literature procedure14 was used to make this compound. Thiophenol (1.10 g, 10 mmol) was added dropwise to a mixture of acrylonitrile (1.06 g, 20 mmol) and tetrabutylammonium hydroxide (40 wt % aq. 0.1 mL) dissolved in dichloromethane (50 mL). The reaction mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The residue was charged onto a silica gel column and eluted with EtOAc/hexane to afford 2-cyanoethyl phenyl sulfide (1.50 g, 92%) as a colorless oil. 1H NMR (CDCl3) δ: 2.59 (t, 2H, J=7.2 Hz), 3.13 (t, 2H, J=7.2 Hz), 7.30-7.45 (m, 5H). 13C NMR (CDCl3) δ: 18.59, 30.58, 127.68, 129.32, 131.37, 133.10. The sulfide (815 mg, 5 mmol) was dissolved in 20 mL DCM and mCPBA (57-86%, 2 g) was added. The reaction mixture was stirred at room temperature for 5 hours and concentrated in vacuo. The residue was washed with saturated aqueous NaHCO3 and extracted with DCM (3×10 mL). The organic phases were combined, dried over MgSO4, concentrated, and charged onto a silica gel column, which was eluted with EtOAc/hexane. 2-Cyanoethyl phenyl sulfoxide was obtained as a white solid (770 mg, 86%). 1H NMR (CDCl3) δ: 2.40-2.60 (m, 11), 2.80-3.00 (m, 2H), 3.10-3.30 (m, 1H), 7.40-7.60 (m, 5H). 13CNMR (CDCl3) δ: 9.95, 50.48, 123.89, 129.59, 131.72, 141.22. Mp 61-62° C. (lit.15 64-65° C.).
4-Methoxydiphenyl sulfoxide: A modified literature procedure16 was used to prepare this compound. To a well stirred suspension of sodium benzenesulfinate (5.41 g, 30 mmol, dried at 100° C. for 2 h.) in cold (ice water bath) dry toluene (30 mL) was added dropwise thionyl chloride (2.98 g, 25 mmol). The reaction mixture was allowed to warm up to room temperature and stirred overnight. Toluene was removed by applying high vacuum (0.5 mmHg) and crude bezenesulfinyl chloride was dissolved in dry DCM (20 mL), cooled to 0-5° C., and was added dropwise to a mixture of anisole (3.24 g, 30 mmol) and anhydrous aluminum chloride (4.0 g, 30 mmol) in DCM (20 mL) at 0-5° C. under nitrogen. This mixture was stirred at 0-5° C. for 3 hours. Water was added slowly and organic phase separated, dried over MgSO4, filtered and concentrated in vacuo to give a pale yellow oil. A hexane wash of the crude material afforded the sulfoxide as a white solid (4.76 g, 82%). 1H NMR (CMCl3) δ: 3.81 (s, 3H), 6.95 (d, 2H, J=9.0 Hz), 7.40-7.48 (m, 3H), 7.55 (d, 2H, J=9.0 Hz), 7.56-7.62 (m, 2H). 13C NMR (CDCl3) δ: 55.74, 114.84, 124.58, 127.21, 129.16, 130.69, 136.78, 145.77, 161.88. Mp 85-86° C. (lit.17 86-89° C.).
Preparation of (R)-methyl p-tolyl suffoxide18 and 18: To a solution of (R)-binaphthol (0.10 mmol) in carbon tetrachloride were added Ti(OiPr)4 (0.050 mmol) and H2O (1.0 mmol) under aerial conditions. After the resulting brown solution was stirred at room temperature for 1 h, methyl p-tolyl sulfide (1.0 mmol) was introduced by a syringe, followed by TBHP (2.0 mmol, 5.0-6.0 M in decane), and the mixture was stirred open to air for 7 h. The reaction mixture was directly submitted to column chromatography with silica gel using 1:1 hexane/ethyl acetate as eluent. HPLC analysis on a Daicel Chiralcel AS column (3:7 iPrOH/hexane, 1.0 mL/min.) gave 93% ee of the R-enantiomer. Electrochemical sulfoximination of this sample was carried out under above conditions and HPLC analysis of the product 18 on AS column (3:7 iPrOH/hexane, 0.50 ml/min.) gave the ee value of 97%.
Electrochemical Sulfoximination Procedure
For the sulfoxide substrate corresponding to each sulfoximine listed in Table 2, the following procedure was followed. The anodic compartment was charged with 1.0 mmol sulfoxide, 210 mg (1.3 mmol) N-aminophthalimide, 78 mg (1.3 mmol) acetic acid (glacial), 130 mg (1.3 mmol) triethylamine, and 20 mL acetonitrile. Portions of 0.05 M AcOH in MeCN were added to the cathodic (20 mL) and reference (4 mL) compartments. Platinum foils (2.5×2.5 cm, 99.99%) were used as working and auxiliary electrodes. Silver wire (1.5 mm dia., 99.99%) was used as a pseudo-reference electrode. The electrolysis was performed at +1.80 V at ambient temperature and was stopped when the cell current dropped to less than 5% of its original value. The contents of anodic compartment were collected and concentrated in vacuo. The residue was washed with water and extracted with dichloromethane (3×5 mL). The organic phases were combined, dried over MgSO4, concentrated, charged onto a silica gel column, and eluted using EtOAc/hexane to afford sulfoximine. The isolated products were characterized, as indicated below.
N-Phthalimido-S,S-dimethylsuffoximine (17):19 1H NMR (CDCl3) δ: 3.29 (s, 6H), 7.67-7.71 (m, 2H), 7.79-7.82 (m, 2H). 13C No (CDCl3) δ: 41.39, 123.38, 130.74, 134.15, 167.44. Mp 205-206° C. (lit.20 208-210° C.).
N-Phthalimido-S-methyl-S-Tolyl)sulfoximine (18):21 1H NMR (CDCl3) δ: 2.43 (s, 3H), 3.33 (s, 3H), 7.35 (d, 2H, J=8.4 Hz), 7.63-7.76 (m, 4H), 8.09 (d, 2H, J=8.4 Hz). 13C NMR (CDCl3) δ: 21.90, 42.86, 123.21, 129.61, 130.08, 130.80, 133.33, 133.91, 145.49, 167.06. Mp 167-169° C. X-ray data for (R)-18 (recrystallized from toluene): C16H14N2O3S, MW=314.35, colorless prismatic crystal, crystal size 0.30×0.12×0.10 mm−1, orthorhombic, space group P21/21/21, a=7.9615(2) Å, b=9.9599(2) Å, c=38.3334(10) Å, V=3039.68(13) Å3, Z=8, dcalc=1.374 g/cm3, F(000)=1312, μ=0.227 mm−1, T=150(1) K, 12041 reflections collected, 6335 independent reflections, R=0.0614, Rw=0.0936, GOF on F2=1.022.
N-Phthallmido-S,S-diphenylsulfoximine (19):22 1H NMR (CDCl3) δ: 7.46-7.58 (m, 6H), 7.60-7.62 (m, 2H), 7.72-7.74 (m, 2H), 8.22-8.28 (m, 4H). 13C NMR (CDCl3) δ: 123.17, 129.36, 129.59, 130.83, 133.82, 133.85, 137.45, 166.81. Mp 218-219° C. (lit. 220-221° C.).
N-Phthalimido-S-phenyl-vinylsulfoximine (20):22 1H NMR (CDCl3) δ: 6.19 (dd, 1H, J=0.9, 9.3 Hz), 6.54 (dd, 1H, J=0.9, 16.5 Hz), 6.86 (dd, 1H, J=9.3, 16.5 Hz), 7.50-7.90 (m, 7H), 8.20-8.30 (m, 2H). 13C NMR (CDCl3) 6:123.27, 129.50, 1-29.57, 130.86, 131.99, 133.98, 134.39, 135.24, 135.93, 167.00. Mp 138-140° C. (lit.20 136-137° C.).
N-Phthalimido-S-benzyl-S-phenylsulfoximine (21): 1H NMR (CDCl3) δ: 4.65 (d, 1H, J=20.7), 4.78 (d, 1H, J=20.7), 7.01-7.94 (m, 14H). 13C NMR (CDCl3) S: 61.19, 123.29, 127.19, 128.65, 129.01, 129.18, 130.67, 130.98, 131.32, 133.89, 134.01, 134.29, 167.33. HRMS 376.0885 (Calc. 376.0882 for C21H16N2O3S). Mp 153-155° C.
N-Phthalimido-S-(2-cyanoethyl)S-phenylsulfoximine (22): 1H NMR (CDCl3) 6:3.01 (t, 2H, J=11.1 Hz), 3.64 (dt, 1H, J=21.5, 11.1 Hz), 3.87 (dt, 1H, J=21.5, 11.1 Hz), 7.64-7.78 (m, 7H), 8.22 (d, 2H, J=11.7 Hz). 13C NMR (CDCl3) S: 12.63, 50.01, 115.90, 123.43, 129.95, 130.11, 130.74, 133.90, 134.22, 135.32, 166.98. HRMS 339.0670 (Calc. 339.0678 for C17H13N3O3S).
N-Phthalimido-S-(4-methoxyphenyl)S-phenylsulfoximine (23): 1H NMR (CDCl3) δ: 3.83 (s, 3H), 6.97 (d, 2H, J=9.3 Hz), 7.48-7.74 (m, 7H), 8.17-8.22 (m, 4H). 13C NMR (CDCl3) δ: 55.83, 114.78, 123.22, 127.86, 129.27, 129.35, 130.85, 132.02, 133.62, 133.92, 138.07, 164.13, 167.07. HRMS 392.0817 (Calc. 392.0831 for C21H16N2O4S).
N-Phthalimidotetramethylene sulfoximine (24): 1H NMR (CDCl3) δ: 2.33-2.44 (m, 4H), 3.14-3.28 (m, 21′), 3.64-3.78 (m, 2H), 7.60-7.90 (m, 4H). 13C NMR (CDCl3) δ: 24.09, 52.90, 123.37, 130.92, 134.16, 167.56. Mp 179-180° C. HRMS 264.0567 (Calc. 264.0569 for C12H12N2O3S).
Electrochemical Aziridination of Olefins.
Recently, Compton and coworkers23 showed that an electrochemical redox cycle involving Pb(IV) and Pb(II) can be realized. The cyclic voltammetry (CV) of Pb(OAc)2 in acetonitrile was found to give a value of +1.60 V (vs. Ag/AgCl) for the oxidation potential of Pb(II) to Pb(IV),23 whereas the CV of N-aminophthalimide (0.01 M in acetonitrile) shows two irreversible one-electron oxidation processes with anodic peak potentials at +1.35 V and at +1.68 V (vs. Ag/AgCl). Using 10 mol % Pb(OAc)2, the electrochemical aziridination of cyclohexene with N-aminophthalimide was conducted at a constant potential of +1.60 V, and gave a 75% isolated yield of 1.
Furthermore, the CV of cyclohexene24 (0.01 M in acetonitrile) has been found to produce an anodic current of −1.3 μA at +1.68 V (vs Ag/AgCl), which is only a small fraction of the current recorded for N-aminophthalimide (−152 μA,
A variety of olefins were subject of aziridination in this process, as summarized in Table 1. Both electron-rich and electron-poor olefins were converted to aziridines electrochemically. For certain monosubstituted terminal olefins (
The aziridination reaction was found not to take place when a graphite electrode was used. The CV study on carbon electrode revealed that anodic current corresponding to the oxidation cyclohexene (−5.3 μA at +1.68 V) was comparable to that of N-aminophthalimide (−15.6 μA at +1.68 V). Such small difference in the rate of electrochemical oxidation apparently does not secure high selectivity in olefin aziridination.
Electrochemical Imination of Sulfoxides
Imination of sulfoxides, to obtain the corresponding sulfoximines, with N-aminophthalimide is known to be mediated by Pb(OAc)4.25 As mentioned above, the CV of N-aminophthalimide (0.01 M in acetonitrile) on a platinum electrode (
The nature of electrode material was found to be important the electrochemical transfer process. The CV (
On the platinum anode, the electrolysis conditions were similar to those of aziridination (Scheme 2 of
Furthermore, this electrochemical nitrene transfer process was found to be stereospecific. An enantiomerically enriched (93% ee of the R-enantiomer)18 sample of methyl p-tolyl sulfoxide was electrolyzed under the conditions described above. The ee value measured for the product sulfoximine 18 was the same (97%) within the error of HPLC analysis and the X-ray structure of the product showed retention of configuration, indicating that no racemization occurred during nitrene transfer process.
Mechanistic Consideration in Electrochemical Aziridination Process
The mechanism of the Pb(OAc)4 mediated olefin aziridination with N-aminophthalimide and other N-amino heterocycles has been studied by Atkinson and coworkers.26 It has been suggested that the oxidation of N-aminophthalimide by Pb(OAc)4 generates an N-acetoxyamino intermediate, which can be isolated or is stable enough to be observed by NMR at low temperature (<5° C.). Addition of olefin at higher temperature to this intermediate results in aziridine (Scheme 3 of
Here, the results obtained in the oxidation of N-aminophthalimide in the presence of olefin with supporting electrolytes other than triethylammonium acetate are shown in Table 3. In cases of LiClO4, Bu4NBF4, and Et4NOTs, no aziridine was detected while phthalimide was isolated in high yields (80-85%). The apparent need for a carboxylate anion of some sort, particularly acetate, for aziridine generation implies that a similar N-acetoxyamino intermediate may be involved in this process. This is also evidenced by the correlation between the aziridine yields and acetate concentrations.
More mechanistic evidence has been obtained by comparing the electrochemical and chemical (Pb(OAc)4 mediated) aziridination results, especially in stereochemical aspects. Dreiding and coworkers28 showed that the Pb(OAc)4 promoted aziridination is stereospecific, i.e., E-olefins afford only the trans-aziridines and Z-olefins only the cis-aziridines. Here, the NMR analysis and X-ray structure of 10 showed exclusive formation of a trans-aziridine. The corresponding Z-olefin, dimethyl maleate, was found to give aziridination product, however, electrochemical aziridination of the E- and Z-1,2-dichloro-2-butene and the results showed that this process is also stereospecific (Table 4, entries 2, 3). Furthermore, the diastereoselectivity of the electrochemical and chemical approaches were found to be comparable (Table 4, entries 4, 5). An exclusive syn-aziridine (shown by its X-ray structure) was obtained for 16.
The continuum of accessible electrode potentials provided by electrochemistry enables differentiating substrates based on their overpotentials.
All citations referred to in this document are incorporated herein by reference in their entirety, as though the contents of each such reference was reproduced in its entirety in this document.
The scope of protection sought for any invention described herein is defined by the claims which follow. It will be appreciated by those skilled in the art that a variety of possible combinations and subcombinations of the various compounds obtainable through the processes described herein exist, and all of these combinations and subcombinations should be considered to be within the inventor's contemplation though not explicitly enumerated here. This is also true of the variety of aspects of the processes and the combinations and subcombinations of elements thereof.
areaction at 0° C.
b2:1 ratio of diastereomers.
c4.4:1 ratio of diastereomers.
aAll aziridination reactions with Pb(OAc)4 were studied by NMR in CD3CN. The products were not isolated and their configurations were determined by comparing with the products from electrochemical reactions.
bX-ray structure.
cNMR study in CDCl3.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/CA02/01163 | 7/25/2002 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 60307809 | Jul 2001 | US |
