Oxidation of Imines by Selenium Dioxide

Oxidation of Imines by Selenium Dioxide Hubert Martin and R udolf 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 [1—6], oxidations by selenium dioxide remained limited to only a few classes of compounds, mainly alkenes and carbonyl compounds, in addition to some special cases [7, 8]. Selenium dioxide is the cheapest and most convenient selenium reagent, and an extension of its applications to other types of com­ pounds is therefore of considerable interest. As the oxidation of carbonyl compounds by S e 0 2 is thought to start with the enolization of the car­ bonyl compound, we suspected that imines, which are capable of forming enamines by a similar tautomerism, might be susceptible to S e 0 2 oxidation. A literature screening revealed only one example of S e 0 2 oxidation of imines. In 1963, Schreiber and Ripperger reported a clean oxidation of two steroid imines by selenium dioxide and obtained iminocholestenones [9]. These authors already supposed the reaction to be general, but no further applica­ tions appeared in the literature.

methanol lead to the formation of various side prod­ ucts not further investigated. In addition, we have found that trapping the water formed in the reaction by adding molecular sieve gives appreciable higher yields. The reaction conditions and yields for the oxida­ tion of a variety of imines are shown in Table I. The structure of the products is clearly indicated by their spectroscopic data (see Table II). Most ketoimines occur as a mixture of E/Z-isomers and show therefore more than one signal for each group in the N M R spectra. This is even more compli­ cated in the case of the cyclic compounds 2 g—i. Their 13C N M R spectra show the presence of the enamine tautomer, according to the following equilibrium: CL

h

A

H

Results and Discussion

Ci

We have now undertaken a systematic study of various imines and found that the reaction indeed is general and proceeds under much milder conditions than the oxidation of the corresponding carbonyl compounds. Am ong the solvents which may be used for the oxidation, diethyl ether is the solvent of choice. In less polar solvents (e.g. benzene or to­ luene), longer reaction times are necessary, while in more polar solvents (e.g. dichloromethane, T H F, dioxane), the separation of precipitated selenium turned out to be more difficult. Protic solvents like * Reprint requests to Dr. R. Herrmann. Verlag der Zeitschrift für Naturforschung, D-7400 Tübingen 0340 - 5087/86/1000 -1260/$ 01.00/0

in

D

n

C

7;n =1 , 8:n=2 , 9:n =3

In chloroform solution, the equilibrium is nearly totally shifted towards the tautomer D (ketoenamine). However, as neat liquid, the IR spectrum indicates that the cyclopentanone derivative exists mainly as iminoenol (tautomer B), as well as the cyclohexanone derivative after some hours of stand­ ing. If freshly distilled, the IR spectrum resembles closely the spectrum of the cycloheptanone derivative and indicates that the compounds are presumably a mixture of the iminoenol B and the ketoimine A . For

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H. Martin—R. Herrmann • Oxidation of Imines by Selenium Dioxide Table I. Oxidation of imines by selenium dioxide. R 2 C O C (R l) - N - R 3 R 2--CHi—C (R ') = N- n3 Se0 2 -Se - H 20 2 1 Time (h), 2 R2 R3 R1 conditions a b c d

H H H H

/Pr /Pr /Pr /Pr

/Bu /Octa CH(/Pr)Fcb CH(/Bu)Fcb

e f g h i j k

H H

/Pr H

Me cHex /Octa rOcta /Octa /Octa

- ( c h 2)3- (C H 2)4— - (C H 2)5— Me «-Pentyl l-Benzyl-3,4-dihydro-6,7dimethoxyisoquinoline a

Isolated yield (% )

m.p. (°C), Remarks b.p. (°C),(mm)

5, r.t. 8 , reflux 12 , reflux

49 56 65 70

80 (16) 38 (0.015) 46-48

6, 4, 1, 15, 1, 4, 12 ,

25° 0d 50 44 51 40 62

65 72 80 87 -

6 , r.t.

r.t. r.t. r.t. reflux r.t. reflux reflux

racemate [a]g’ = -71.7 ( c = l, E tO H )

(0.015) (0.015) (0.015) (0.015) see [10]

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

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

‘H N M R (d)a

13C N M R b

c=o

C=N

C=C

IR v(cm _1)c

Mass spectra (70 eV)d

a

7.50 (s)

205.89

158.36e 153.49

-

1700 (vs) 1650 (sh)

m + = 155 (calc, for C 9H 17NO: 155.24)

b

7.42 (s)

206.15

157.91e 153.95

-

1700 (vs) 1670 (vs)

m + = 211 (calc, for C 13H 25NO: 211.35)

c

7.67 (s) 4.00 (s)f

205.63

157.52

-

1700 (vs) 1675 (vs)

m + = 339 (calc, for C „ H 25FeNO: 339.26)

d

7.77 (s) 4.00 (s)f

205.63

157.52

-

1700 (vs) 1675 (vs)

m + = 353 (calc, for C 20H 27FeNO: 353.29)

e

7.03 (s)

-

-

-

1700 (vs) 1650 (m)

itT

g

6.00 (tr)

205.70

-

142.39 120.31

1700 (vs) 1635 (vs)

m + = 209 (calc, for C 13H 23NO: 209.33)

h

5.60 (tr) 4.28 (s, br)

196.42

138.30 128.76

1715 1670 1625 1710 1625 1670

m + = 223 (calc, for C 14H 25NO: 223.36)

i

5.63 (tr) 4.06 (s, br)

201.09

142.78 113.95

1700 (m) 1660 (vs) 1615 (s)

m + = 237 (calc, for C 15H 27NO: 237.38)

-

1665-1690 (vs, br)

m + = 253 (calc, for C 1(SH 31NO: 253.43)

—

1675 (s) 1605 (vs)

m + = 295 (calc, for C i8H 17NO: 295.34)

3.97 (s, br)

j

207.56

k

193.82

153.62d 147.86

(m)g (vs)® (s)g (sh)h (vs)h (vs)h

= 113 (calc, for C 6H u NO: 113.16)

a In CD C I 3 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.

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H. Martin —R. Herrmann • Oxidation of Imines by Selenium Dioxide

the occurrence of tautomer C (diene), we do not have clear indications. This obvious solvent dependence of the structure of the cyclic oxidation products will al­ low their application as versatile starting materials for further synthesis [11]. The reactivities of the imines vary considerably, but are generally much higher than those of the cor­ responding aldehydes and ketones. If, for instance, an equimolar mixture of 3-methylbutanal and its imine with /-butylamine is allowed to react with one equivalent of selenium dioxide, only the presence of the 2-oxoimine can be detected after 5 hours at room temperature, but no 2-ketoaldehyde. Bulky sub­ stituents at nitrogen do not lower the reactivity, but, on the contrary, lead to cleaner products and higher yields (2 a —e). The reaction is highly selective, the reactivity of C —H bonds decreases in the direction C H 2 > C H 3 > C H . Thus, the imine of 2-octanone gives the 3-ketoimine upon oxidation, but no 2-iminoaldehyde. This contrasts sharply with the behaviour of ketones, where the reactivity of methyl groups exceeds that of methylene groups considerably [8]. C H groups as in the imines of 2-methylpropanal are not attacked by S e 0 2 in ether during one day at room temperature. This high degree of selectivity, together with the very mild reaction conditions, allows the introduc­ tion of keto groups a to imino functions in the pres­ ence of many other functional groups [11]. The mechanism of the oxidation is assumed to be similar to the S e 0 2 oxidation of carbonyl compounds [12]. Thus, the first step is the 3-aza-ene reaction [13, 14] of the enamine tautomer of the imine with the enophilic [8] selenium-oxygen double bond of selenium dioxide, leading to a /?-imino-selenic acid [12]. Loosing water and selenium, this intermediate decomposes to the final product. As we have tried to minimize the water content in the reaction mixture by adding molecular sieve, we believe that selenium dioxide itself and not selenous acid is the active reagent, although it is known that the surface of crystalline S e 0 2 contains much selen­ ous acid if moisture is not rigorously excluded [15]. The different reaction conditions used for the oxida­ tion of imines on the one hand and ketones on the other may also account for the striking differences in the reactivity of cyclic ketones and their imines. In water/acetic acid, cyclohexanone is oxidized more rapidly the cycloheptanone and cyclopentanone [8, 16], In contrast, the imines of cyclopentanone

and cycloheptanone are oxidized completely in one hour at room temperature, while the imine of cyclo­ hexanone needs 15 hours in refluxing ether. The amount of enamine present in the imine is not indicative for the reactivity: The six-membered cyclic imine contains more enamine than the five- and seven-membered analogues, as observed in the case of the cyclic ketones [17] (in cyclohexylidene-r-butylamine, the imine contains between 11 and 25% of enamine [18], and the same can be expected for the imine lh ) . Previous methods for the preparation of a-ketoimines had a very limited scope. The direct reaction of a-dicarbonyl compounds with amines was success­ ful only with symmetrical diketones [19, 20] or with methyl- or phenylglyoxal [20, 21]. The oxidation of suitable precursors, e.g. /3-aminoketones, with lead tetraacetate, is limited mainly to aromatic systems [22]. Molecular oxygen has been used to oxidize 3,4dihydroisoquinolines to the corresponding ketoimines [10], but in comparatively low yields. A re­ cent publication describes the preparation of 1-acyl3,4-dihydroisoquinolines via the addition of a-ketoimidoyl halides to phenylethyl isocyanides [23]. The ease of the formation of such compounds by our method (compare 2 k) will provide new precursors for alkaloid synthesis, e.g. in the aporphine and erythrinane field [24]. The introduction of two sulfide moieties at the a-carbon of cyclic iminoethers, which is a formal oxidation of this atom, via the carbanion, is not of general applicability [25], although it may be considered as a supplement to the S e 0 2 oxidation. O ur attempts to oxidize 2-methoxypyrroline by S e 0 2 led only to decomposition products, as well as the oxidation of the cyclic amidine 1,5-diazabicyclo[4.3.0]non-2-ene. Reports on the oxidation of nitrogen compounds with selenium dioxide are rather scarce. 0-Alkyloximes give 2-alkoxyimino aldehydes and ketones, although overoxidation to carboxylic acid derivatives has often been observed which limits the generality of the method [26]. The hydrazones of carbonyl com­ pounds with electronically poor hydrazines can be oxidized in the same manner as imines [27]. H ow ­ ever, good yields are obtained only in cases where the structure of the hydrazone does not allow side reactions like the formation of a,/?-unsaturated imines. Otherwise, mixtures of products are formed. Generally, the reaction of hydrazones [28] and semicarbazones [29, 30] with S e 0 2 leads to selenium in-

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H. Martin —R. Herrmann • Oxidation of Imines by Selenium Dioxide

Corporation in the molecule to form selenium heterocycles. The S e 0 2 oxidation of imines is limited only by a few structural features. E.g. the methylene group of 2-phenyl-azirine is inert under the reaction condi­ tions, and imines of acetaldehyde give only intractible materials. Despite this limitations, the S e 0 2 oxidation of imines is the most general method for the preparation of a-iminoaldehydes and a-iminoketones which are interesting synthetic building blocks in organic chemistry [31—33].

Experimental 'H N M R spectra have been recorded with a Jeol P M X 60 and 13C N M R spectra with a Jeol JN M FX-60 instrument, and IR spectra with a PerkinElmer 157 G instrument. Mass spectra have been ob­ tained with a Varian C H 5 instrument. The imines used as starting materials have been prepared by standard methods. New imines are listed in Table III.

Oxidation of imines by Se0 2 The imine (10 mmol) is dissolved in 30 ml of di­ ethyl ether, and 5.0 g of molecular sieve (3 Ä ) and 11 mmol (1.22 g) of selenium dioxide (used as pur­ chased) are added. The mixture is stirred with exclu­ sion of moisture for the time and under the condi­ tions indicated in Table I. After filtering, the prod­ uct is distilled under vacuum or purified by the addi-

[1] D. H. R. Barton, X. Lusinchi, and P. Milliet, Tet­ rahedron 41, 4727 (1985). [2] F. A. Davis, O. D. Stringer, and J. P. McCauley (Jr.), Tetrahedron 41, 4747 (1985). [3] A. Ogawa, N. Kambe, S. Murai, and N. Sonoda, Tetrahedron 41, 4813 (1985). [4] A. P. Kozikowski and A. Ames, Tetrahedron 41, 4821 (1985). [5] D. Seebach, G. Calderari, and P. Knöchel, Tetra­ hedron 41, 4861 (1985). [6 ] D. Liotta, M. Saindane, C. Barnum, and G. Zima, Tetrahedron 41, 4881 (1985). [7] E. N. Trachtenberg, Selenium Dioxide Oxidation, in R. L. Augustine (ed.): Oxidation, Vol. 1, Marcel Dekker, New York 1969. [8] H. J. Reich, Organoselenium Oxidations, in W. S. Trahanovsky (ed.): Oxidation in Organic Chemistry, Part C, Academic Press, New York — San Francisco — London 1978. [9] K. Schreiber and H. Ripperger, Chem. Ber. 96, 3094 (1963).

Table III. Preparation and characteristic spectroscopic data of imines l a. Imineb Isolated b.p. (°C) yield (% ) (mm)

'H N M R (