Oxidation of Imines by Selenium Dioxide

Hubert Martin and Rudolf Herrmann* Organisch-Chemisches Institut der Technischen Universität München, Lichtenbergstraße 4, D-8046 Garching Z. Naturforsch. 41b, 1260—1264 (1986); received May 25, 1986 Selenium Dioxide, Imines, a-Imino Carbonyl Compounds The oxidation of imines containing a a-methylene group by selenium dioxide is investigated. The products are shown to be a-imino carbonyl compounds by spectroscopic methods. The reactivity of various imines is discussed.

Despite the current interest in selenium chemistry methanol lead to the formation of various side prod­ [1—6], oxidations by selenium dioxide remained ucts not further investigated. In addition, we have limited to only a few classes of compounds, mainly found that trapping the water formed in the reaction alkenes and carbonyl compounds, in addition to by adding molecular sieve gives appreciable higher some special cases [7, 8]. Selenium dioxide is the yields. cheapest and most convenient selenium reagent, and The reaction conditions and yields for the oxida­ an extension of its applications to other types of com­ tion of a variety of imines are shown in Table I. pounds is therefore of considerable interest. The structure of the products is clearly indicated As the oxidation of carbonyl compounds by Se02 by their spectroscopic data (see Table II). is thought to start with the enolization of the car­ Most ketoimines occur as a mixture of E/Z-isomers bonyl compound, we suspected that imines, which and show therefore more than one signal for each are capable of forming enamines by a similar tautom- group in the N M R spectra. This is even more compli­ erism, might be susceptible to S e 0 2 oxidation. cated in the case of the cyclic compounds 2 g—i. A literature screening revealed only one example Their 13C N M R spectra show the presence of the of Se02 oxidation of imines. In 1963, Schreiber and enamine tautomer, according to the following Ripperger reported a clean oxidation of two steroid equilibrium: imines by selenium dioxide and obtained imino- cholestenones [9]. These authors already supposed CL the reaction to be general, but no further applica­ tions appeared in the literature. h A

Results and Discussion H Ci We have now undertaken a systematic study of

various imines and found that the reaction indeed is in D n C general and proceeds under much milder conditions 7;n =1 , 8:n=2 , 9:n=3 than the oxidation of the corresponding carbonyl compounds. Among the solvents which may be used for the oxidation, diethyl ether is the solvent of In chloroform solution, the equilibrium is nearly choice. In less polar solvents (e.g. benzene or to­ totally shifted towards the tautomer D (ketoen- luene), longer reaction times are necessary, while in amine). However, as neat liquid, the IR spectrum more polar solvents (e.g. dichloromethane, THF, indicates that the cyclopentanone derivative exists dioxane), the separation of precipitated selenium mainly as iminoenol (tautomer B), as well as the turned out to be more difficult. Protic solvents like cyclohexanone derivative after some hours of stand­ ing. If freshly distilled, the IR spectrum resembles * Reprint requests to Dr. R. Herrmann. closely the spectrum of the cycloheptanone derivative Verlag der Zeitschrift für Naturforschung, D-7400 Tübingen and indicates that the compounds are presumably a 0340 - 5087/86/1000 -1260/$ 01.00/0 mixture of the iminoenol B and the ketoimine A. For H. Martin—R. Herrmann • Oxidation of Imines by Selenium Dioxide 1261

Table I. Oxidation of imines by selenium dioxide.

Se R2--CHi—C(R') = N- n3 0 2 R 2 CO C (R l)- N - R 3 -Se - H 20 1 2 2 R 1 R 2 R 3 Time (h), Isolated m.p. (°C), Remarks conditions yield (%) b.p. (°C),(mm) a H /Pr /Bu 6 , r.t. 49 80 (16) b H /Pr /Octa 5, r.t. 56 38 (0.015) c H /Pr CH(/Pr)Fcb 8, reflux 65 - racemate d H /Pr CH(/Bu)Fcb 12, reflux 70 46-48 [a]g’ = -71.7 (c=l, EtOH) e H /Pr Me 6 , r.t. 25° f H H cHex 4, r.t. 0d g -(c h 2)3- /Octa 1 , r.t. 50 65 (0.015) h - (C H 2)4— rOcta 15, reflux 44 72 (0.015) i -(C H 2)5— /Octa 1 , r.t. 51 80 (0.015) j Me «-Pentyl /Octa 4, reflux 40 87 (0.015) k l-Benzyl-3,4-dihydro-6,7- 12, reflux 62 - see [10] dimethoxyisoquinoline

a /Oct = 1,1,3,3-tetramethylbutyl; b Fc = Ferrocenyl; c yield calculated from NMR; not isolated; d formation of tar.

Table II. Characteristic spectroscopic data of the oxidation products 2.

2 ‘H NM R (d)a 13C N M Rb IR v(cm_1)c Mass spectra (70 eV)d c = o C =N C = C

a 7.50 (s) 205.89 158.36e - 1700 (vs) m+ = 155 153.49 1650 (sh) (calc, for C9H 17NO: 155.24) b 7.42 (s) 206.15 157.91e - 1700 (vs) m+ = 211 153.95 1670 (vs) (calc, for C 13H 25NO: 211.35) c 7.67 (s) 205.63 157.52 - 1700 (vs) m+ = 339 4.00 (s)f 1675 (vs) (calc, for C „H25FeNO: 339.26) d 7.77 (s) 205.63 157.52 - 1700 (vs) m + = 353 4.00 (s)f 1675 (vs) (calc, for C20H 27FeNO: 353.29) e 7.03 (s) -- - 1700 (vs) itT = 113 1650 (m) (calc, for C6H uNO: 113.16)

g 6.00 (tr) 205.70 - 142.39 1700 (vs) m+ = 209 3.97 (s, br) 120.31 1635 (vs) (calc, for C 13H 23NO: 209.33) h 5.60 (tr) 196.42 138.30 1715 (m)g m+ = 223 4.28 (s, br) 128.76 1670 (vs)® (calc, for C 14H 25NO: 223.36) 1625 (s)g 1710 (sh)h 1625 (vs)h 1670 (vs)h i 5.63 (tr) 201.09 142.78 1700 (m) m+ = 237 4.06 (s, br) 113.95 1660 (vs) (calc, for C 15H 27NO: 237.38) 1615 (s)

j 207.56 153.62d - 1665-1690 m+ = 253 147.86 (vs, br) (calc, for C 1(SH 31NO: 253.43) k 193.82 — 1675 (s) m+ = 295 1605 (vs) (calc, for C i8H 17NO: 295.34)

a In CDCI3 at 60 MHz;2a—e: signal of H —C= ; 2g—k: signals of the enamine group; b in CDC1, at 15 MHz; c double bond region; d all new compounds gave satisfactory analytical data (C ±0.34, H ±0.20, N ±0.22);e E/Z isomers;f signal of unsubstituted cp of ferrocene;g directly after distillation; h after 3 hours at room temperature; 1 signal not separated from the signals of the aromatic system. 1262 H. Martin —R. Herrmann • Oxidation of Imines by Selenium Dioxide the occurrence of tautomer C (diene), we do not have and cycloheptanone are oxidized completely in one clear indications. This obvious solvent dependence of hour at room temperature, while the imine of cyclo­ the structure of the cyclic oxidation products will al­ hexanone needs 15 hours in refluxing ether. low their application as versatile starting materials for The amount of enamine present in the imine is not further synthesis [11]. indicative for the reactivity: The six-membered cyclic The reactivities of the imines vary considerably, imine contains more enamine than the five- and but are generally much higher than those of the cor­ seven-membered analogues, as observed in the case responding aldehydes and ketones. If, for instance, of the cyclic ketones [17] (in cyclohexylidene-r-butyl- an equimolar mixture of 3-methylbutanal and its amine, the imine contains between 11 and 25% of imine with /-butylamine is allowed to react with one enamine [18], and the same can be expected for the equivalent of selenium dioxide, only the presence of imine lh ). the 2-oxoimine can be detected after 5 hours at room Previous methods for the preparation of a-keto- temperature, but no 2-ketoaldehyde. Bulky sub­ imines had a very limited scope. The direct reaction stituents at nitrogen do not lower the reactivity, but, of a-dicarbonyl compounds with amines was success­ on the contrary, lead to cleaner products and higher ful only with symmetrical diketones [19, 20] or with yields (2a—e). methyl- or phenylglyoxal [20, 21]. The oxidation of The reaction is highly selective, the reactivity of suitable precursors, e.g. /3-aminoketones, with lead C —H bonds decreases in the direction C H 2 > C H 3 > tetraacetate, is limited mainly to aromatic systems CH . Thus, the imine of 2-octanone gives the 3-keto- [22]. Molecular oxygen has been used to oxidize 3,4- imine upon oxidation, but no 2-iminoaldehyde. This dihydroisoquinolines to the corresponding keto- contrasts sharply with the behaviour of ketones, imines [10], but in comparatively low yields. A re­ where the reactivity of methyl groups exceeds that of cent publication describes the preparation of 1-acyl- methylene groups considerably [8]. CH groups as in 3,4-dihydroisoquinolines via the addition of a-keto- the imines of 2-methylpropanal are not attacked by imidoyl halides to phenylethyl isocyanides [23]. The S e 0 2 in ether during one day at room temperature. ease of the formation of such compounds by our This high degree of selectivity, together with the method (compare 2 k) will provide new precursors very mild reaction conditions, allows the introduc­ for alkaloid synthesis, e.g. in the aporphine and ery- tion of keto groups a to imino functions in the pres­ thrinane field [24]. The introduction of two sulfide ence of many other functional groups [11]. moieties at the a-carbon of cyclic iminoethers, which The mechanism of the oxidation is assumed to be is a formal oxidation of this atom, via the carbanion, similar to the Se02 oxidation of carbonyl compounds is not of general applicability [25], although it may be [12]. Thus, the first step is the 3-aza-ene reaction considered as a supplement to the Se02 oxidation. [13, 14] of the enamine tautomer of the imine with Our attempts to oxidize 2-methoxypyrroline by S e02 the enophilic [8] selenium-oxygen double bond of led only to decomposition products, as well as the selenium dioxide, leading to a /?-imino-selenic acid oxidation of the cyclic amidine 1,5-diazabicyclo- [12]. Loosing water and selenium, this intermediate [4.3.0]non-2-ene. decomposes to the final product. Reports on the oxidation of nitrogen compounds As we have tried to minimize the water content in with selenium dioxide are rather scarce. 0-Alkyl- the reaction mixture by adding molecular sieve, we oximes give 2-alkoxyimino aldehydes and ketones, believe that selenium dioxide itself and not selenous although overoxidation to carboxylic acid derivatives acid is the active reagent, although it is known that has often been observed which limits the generality the surface of crystalline S e02 contains much selen­ of the method [26]. The hydrazones of carbonyl com­ ous acid if moisture is not rigorously excluded [15]. pounds with electronically poor hydrazines can be The different reaction conditions used for the oxida­ oxidized in the same manner as imines [27]. How­ tion of imines on the one hand and ketones on the ever, good yields are obtained only in cases where other may also account for the striking differences in the structure of the hydrazone does not allow side the reactivity of cyclic ketones and their imines. In reactions like the formation of a,/?-unsaturated water/acetic acid, cyclohexanone is oxidized more imines. Otherwise, mixtures of products are formed. rapidly the cycloheptanone and cyclopentanone Generally, the reaction of hydrazones [28] and semi- [8, 16], In contrast, the imines of cyclopentanone carbazones [29, 30] with S e02 leads to selenium in- H. Martin —R. Herrmann • Oxidation of Imines by Selenium Dioxide 1263

Corporation in the molecule to form selenium Table III. Preparation and characteristic spectroscopic heterocycles. data of imines l a.

The S e 0 2 oxidation of imines is limited only by a Imineb Isolated b.p. (°C) 'H NM R (<5)c I3C N M R d few structural features. E.g. the methylene group of 1 yield (%) (mm) H —C= C=N 2-phenyl-azirine is inert under the reaction condi­ a 59 40 (16) 7.50 (tr) tions, and imines of acetaldehyde give only intrac- 158.02 b 55 86 (16) 7.52 (tr) 157.91 tible materials. Despite this limitations, the S e 0 2 c 80 - 7.70 (tr) 162.59 oxidation of imines is the most general method for de 84 - 7.83 (tr) 162.46 the preparation of a-iminoaldehydes and a-imino- g 49 53 (0.015) - 174.01 h 42 58 (0.015) - 169.47 ketones which are interesting synthetic building i 47 67 (0.015) - 170.96 blocks in organic chemistry [31—33]. j 48 70 (0.015) - 165.31

a All new imines gave satisfactory microanalytical data Experimental (C ±0.35, H ±0.30, N ±0.28) and consistent mass spectra; b compounds l a —d: prepared from aldehyde and amine by 'H N M R spectra have been recorded with a Jeol removal of water with molecular sieve (3 Ä) from CC14 PM X 60 and 13C N M R spectra with a Jeol JN M solution; compounds 1 g—j: prepared from ketone and amine by azetotropic water removal (benzene);c in CDC1 FX-60 instrument, and IR spectra with a Perkin- 3 at 60 MHz; d in CDC1, at 15 MHz; e [a]g = -50.2 (c=l, Elmer 157 G instrument. Mass spectra have been ob­ EtOH). tained with a Varian CH5 instrument. The imines used as starting materials have been prepared by standard methods. New imines are listed tion of a small quantity of charcoal (0.3—0.5 g) to the in Table III. ether solution to remove red selenium, filtering and evaporation of the solvent. Yields and properties of Oxidation of imines by Se02 the compounds obtained are collected in Tables I The imine (10 mmol) is dissolved in 30 ml of di­ and II. ethyl ether, and 5.0 g of molecular sieve (3 Ä ) and 11 mmol (1.22 g) of selenium dioxide (used as pur­ The authors wish to thank Prof. Dr. Ivar Ugi, TU chased) are added. The mixture is stirred with exclu­ München, for supporting this work, Mr. Josef Eben- sion of moisture for the time and under the condi­ beck for the rapid l3C NM R measurements, and Dr. tions indicated in Table I. After filtering, the prod­ Reinhard Bussas, Max-Planck-Institut für Q u a n ­ uct is distilled under vacuum or purified by the addi- tenoptik, Garching, for helpful discussions.

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