Electrochemical oxidation of 4-substituted N,N-dimethylaniline in the

Electrochemical oxidation of 4-substituted N,N-dimethylaniline in the presence of silyl en01 ether. Effect of the substituent on the formation of Mannich bases. 11.'

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ROGERN. R E N A U DCAMPBELL ,~ J. STEPHENS,AND GAETAN BROCHU Division of Chemistry, National Research Council, O~tawa,Ont., Canada K I A OR6 Received June 27, 1983 CAMPBELL J. STEPHENS, and GAETANBROCHU. Can. J. Chem. 62, 565 (1984). ROGERN. RENAUD, The formation of Mannich bases from the electrochemical oxidation of 4-substituted N,N-dimethylaniline in the presence of silyl en01 ether was studied. The yield of bases obtained depended on the relative oxidation potentials of the starting amine compound and the base formed. An electron-donating substituent on the amine showed a large difference in the oxidation potentials and gave the highest yield of product. On the other hand, the oxidation potentials were very close with an electron-withdrawing substituent and the yield in base was relatively much lower. Furthermore, the main product in the case of an electron-withdrawing group in the presence of 1-trimethylsilyloxy-I-cyclohexenewas 4-substituted 2-(2-oxocyclohexyl)N,N-dimethylaniline. Some side products were also isolated and were identified as N,N-diketonic compounds. ROGER N. RENAUD, CAMPBELL J. STEPHENS et GAETAN BROCHU. Can. J. Chem. 62, 565 (1984). On a CtudiC la formation des bases de Mannich par oxydation tlectrochimique de N,N-dimethylanilines substitutes en position 4 en presence d'tthers tnoliques silylts. Les rendements en bases dependent des potentiels relatifs d'oxydation des amines de depart et des bases formCes. Un substituant Clectrodonneur sur I'amine provoque une grande difftrence dans les potentiels d'oxydation et conduit un rendement plus ClevC en produit. D'un autre cotC, avec des substituants Clectroaffinitaires, les potentiels d'oxydation sont trks voisins et les rendements en base sont relativement beaucoup plus faibles. De plus, le produit majoritaire obtenu dans le cas d'un reactif portant un groupe Clectroaffinitaire rtaggisant en prtsence du trimCthylsilyloxy-1 cyclohexkne- 1 est une(oxo-2 cyclohexy1)-2 N,N-dimtthylaniline substitute en position 4. On a Cgalement isolC quelques produits secondaires et on les a identifies comme Ctant des composCs N,N-dicetoniques. [Traduit par le journal]

The first paper of this series (1) described the synthesis of Mannich bases from the electrochemical oxidation of N,Ndimethylmesidine in the presence of silyl en01 ethers. It was noticed that the reaction depended upon the relative electrochemical oxidation potentials of the silyl en01 ether, the amine, and the product. In this paper, a selection of 4-substituted N,N-dimethylanilines was chosen in order to examine the effect of the substituent on the formation of the Mannich base:

la b c d e

X = CH, X = OCH, X = COOCH3 X = COCH, X = H

'NRCC No. 22856. ' ~ u t h o rto whom correspondence should be addressed.

Results and discussion In order to compare the effect of the substituent on the yield of Mannich base formed, the experimental conditions for all the runs were kept constant. The only variable was the reaction oxidation potential (E). This potential was controlled at such a voltage that a current of 100 mA was attained at the beginning of the electrolysis (Fig. 1, arrows). Then, the current dropped slowly to about 50 mA or less after the passage of 2 F/mol. The silyl en01 ethers chosen for this study, l-trimethylsilyloxy-1-cyclohexene 3 and l-phenyl-l-trimethylsilyloxyethylene 4, are known from the previous study to give good yield of Mannich bases in the presence of the iminium salt of N,N-dimethylmesidine. The halfwave potentials (E,,?'s) of the two silyl en01 ethers are 1.25 V and 1.30 V vs. Ag/AgN03 respectively. The Eli2'sof the amino compounds 1 are shown in Table 1 and they are all much less anodic than those of the silyl en01 ethers 3 and 4. On the other hand, the halfwave potentials of the amines 1 are, as expected, relatively more anodic for an electron-withdrawing substituent than for an electron-donating substituent. The yield of products 5 and 8 was markedly higher with an electron-donating group (Tables 1 and 2).

I

I

X

X 5

8

The oxidation potentials of at least three compounds must also be considered: the silyl en01 ether, the amine 1, and the Mannich base formed. As for the silyl en01 ethers 3 and 4, their E's are somewhat much too anodic to affect the result of the

CAN. J. CHEM. VOL. 62, 1984

structure of l l c was determined by nuclear magnetic resonance spectroscopy. Two structures are plausible:

llc

llc'


The broad singlet for the proton at the position 2 is at the low field side of the AB system of the two protons at positions 5 and 6. Therefore, it corresponds to a proton ortho to the carbonyl group (structure l l c ) . A proton at position 3 (structure llc') would show the singlet at the high-field side of the AB system. No product corresponding to 5d was observed from Id. The main compounds isolated, in this case, were the amine Id, the product l l d , and polymers. The mechanism for the formation of 11 is still not clear but it is most likely the attack of a radical intermediate a on the silyl en01 ether to give a stabilized ether radical b (2, 3).

w+

CH3,

+

/CH3

/

COR b FIG. 1. Current-potential curves of 4-substituted N,N-dimethylanilines and the corresponding Mannich bases. The arrows indicate the reaction oxidation potentials E. Concentration: scan rate: 2 mV/s.

I

reaction. Therefore, the relative E's of the amine 1 and the products 5 and 8 are most important. The current-potential curves for the amine 1 and the products 5 and 8 are shown in Fig. 1. The E's of the amines having an electron-donating substituent (la and lb) are more cathodic than the E's of the corresponding products 5 and 8 (Fig. 1, arrows) and the Mannich bases were obtained in good yield. However, the difference between the E's of the amine l c and the product 5c was very small and the yield in Mannich base was low. The main compound obtained from this reaction was methyl 3-(2-oxocyclohexyl)-4-N,N-dimethylaminobenzoate l l c . The

CH3,

/CH3

/

COR 11

The electrochemical oxidation of lc- l e in the presence of the silyl en01 ether 4 gave low yields of 8c-8e as the main products. No compound corresponding to 11 was observed. Besides the major products 5 and 8, some side products 6, 7, 9, and 10 were also obtained in low yield. They are formed as a result of further oxidation of 5 and 8 to give a new iminium salt, which reacts either with another molecule of silyl en01 ether to give 6 and 9 respectively or with residual water in the medium to give 7 and 10 respectively. Compounds 7. and 10 may also be formed from the hydrolysis of the iminium salt formed from 1, followed by the electrolysis of the resulting N-methylaniline derivative3 to give another iminium salt which 'The infrared spectrum showed that the starting compound l b was free of rnonomethylanisidine.

RENAUD ET AL

TABLE1. Controlled potential electrolysis of p-substituted N,N-dimethylanilines in the presence of l-trimethylsilyloxy-1-cyclohexane 3 Product 6, 7, or 11

Product 5 Amine 1


la lb lc Id le

X

El,,

Ea (V vs. Ag/AgNO,)

CH3 OCH3 COOCH3 COCH3 H

0.34 0.28 0.72 0.81 0.49

0.26 0.16 0.57 0.60 0.34

5a 56 5c 5d Polymers

Melting point ("C)

Yield

E,,,

27-28 Oil 82-83

50.5 34.6 6.4

0.48 0.30 0.79

-

-

-

6a 7b llc lld

Melting point ("C)

Yield

96-97 61-62 Oil 93-94

13.8 13.1 16.7 20.0

0.47 0.31 0.81 0.83

"The reaction potential.

TABLE 2. Controlled potential of p-substituted N,N-dimethylamilines in the presence of l-phenyl-l-trimethylsilyolxyethylene 4 Product 8 Amine 1

X

Melting point ("C)

Ea E I , ~ (V vs. Ag/AgNO,)

Yield

Product 9 or 10 Melting point ("C)

El,,

Yield

E,,,

"The reaction potential. T h e same yield was obtained using collidine instead of sodium carbonate

7,lO Y

=

ketonic substituent

can react with the silyl en01 ether. The yields of compounds 6c, 6d, and 9d were very low and these compounds could not be obtained pure enough for identification. However, 6a, 9a, and 9c were isolated pure, and identified. With X = OCH, ( l b ) , demethylated product 7 b and a mixture of 9b and lob in a 1 : 1 ratio were obtained.

Experimental The para-substituted N,N-dimethylanilines were obtained from Aldrich or prepared by the methylation ofpara-substitued anilines (4). The silyl en01 ethers were prepared according to methods described in the literature (5). The acetonitrile was purified as reported in the literature (6). Flash chromatography was performed using silica gel 230-400 mesh (7). All melting points reported are uncorrected.

Infrared spectra were recorded on a Perkin-Elmer Model 267 spectrophotometer. Proton magnetic resonance spectra were taken in deuteriochloroform on a Varian Associates spectrometer model E.M. 360 or a Bucker WP-80 apparatus and are reported in the 6 scale. The mass spectra were obtained from a Hewlett-Packard model 5585 gc-ms spectrometer or from a VG 7070 type mass spectrometer. The molecular weight determinations were done on a Mechrolab vapor pressure osmometer model 301A. The electrochemical instrumentation is described in the previous publication (1) with two modifications. The source of energy for the preparative scale synthesis was obtained from a 100-V 10-A Kepco power supply and the potential of the working electrode was controlled by an esc potentiostatic controller model 410. General procedure The anodic solution was a well-stirred mixture of LiCIOl (1.34 g), Na2C03 (2.12 g), silyl en01 ether (3 mL), and para-substituted


568

CAN. J. CHEM.

N,N-dimethylaniline (0.005 mol) in acetonitrile (125 mL). The cathodic solution was LiC104 (0.1 M) in acetonitrile. The potential was controlled at such a voltage that 100 mA was obtained. That potential was kept constant until 2 F/mol has been passed. At the end of the electrolysis the current dropped to about 50 mA. The anodic solution was filtered and concentrated on a high vacuum system. The solvent was collected in a cold trap. The oily residue was extracted with two 100-mL portions of boiling n-pentane or until the pentane solution was negative to tlc. Sometimes an extraction with ether was necessary, but less pure product was isolated. The organic solvent was removed on the vacuum system and the residue pumped under a pressure of lo-' Torr for 3-5 h at room temperature in order to remove the excess of silyl en01 ether. The combined low vapor pressure oil or solid was fractionated by flash chromatography (7) using a column of 2-cm diameter by 40 cm long. The residue of the different fractions was purified further either by a bulb-to-bulb distillation at lo-' Torr or by recrystallization from ethanol in a Craig tube. Physical properties of the products (A) Electrolysis of the amine 1 in the presence of l-trimethylsilyloxy-1-cyclohexene 3 From l a : the crude mixture, obtained after the evaporation of the high vapor pressure fraction, showed one major and three minor spots on the tlc plate. The separation of the products by flash chromatography using hexane - ethyl acetate (8: 1) gave four fractions. First fraction: a very small quantity of starting amine l a . Second fraction: an oil corresponding to 5a. It was further purified by a bulb-to-bulb distillation at 80°C under a pressure of lo-' Torr to give 0.54 g (50.5%) of a white solid melting at 27-28°C; ir (CHCI,): 1710 (C=O) cm-'; 'H nmr 6: 1.70 (broad m including the aromatic CH, group, 12H), 2.90 (s, 3H), 3.42 (AB q, 2H), 6.86 (AB q, 4H); ms m/e: 231 (M+, 29), 134 (M+ - C6H90, 100). Anal. calcd. for C15HZINO:C 77.92, H 9.09, N 6.06; found: C 77.88, H 9.26, N 6.17. Third fraction: a white solid (0.21 g; 13.8%) melting at 96-97°C which corresponded to 6a; ir (CHCI,): 1705 (C=O) cm-'; 'H nmr 6: 1.20-3.90 (broad m including the aromatic CH, group, 25H), 7.02 (q, AB, 4H); ms m/e: 327 (M', lo), 2.30 (M+ - C6H90, 100). Anal. calcd. for CZlHzrN02: C 77.06, H 8.87, N 4.28; found: C 76.96, H 8.88, N 4.37. Fourth fraction: impure oil (7a) (10 mg); ir (neat): 3400 (NH), 1705 (C=O) cm-I; ms m/e: 217 (M', 5) 129 (M' - C6HjC)O, 100). From lb: the oily residue (1.07 g) obtained after the removal of the high vapor pressure fraction showed one major and one minor spots on the tlc plate. Two fractions were obtained by flash chromatography. First fraction: an oil corresponding to 5b. It was purified further by a bulb-to-bulb distillation at 60°C under a pressure of lo-' Torr to give a yellow oil (0.43 g; 34.6%); ir (film): 1703 (C=O) cm-'; 'H nmr 6: 1.20-2.45 (m, 9H), 2.83 (s, 3H), 3.15 and 3.86 (2d, AB, 2H), 3.70 (s, 3H), 6.71 (m, 4H); ms m/e: 247 (M+, 19) 150 (M' - C ~ H Y O100). , Anal. calcd. for Cl,H21N02:C 72.87, H 8.50, N 5.67; found: C 73.41, H 8.56, N 5.51. Second fraction: a white solid melting at 61-62°C after a bulb-to-bulb distillation at 100°C (lo-' Torr). The compound analyzed as 7b (154 mg; 13.1%); ir (CHCI,): 3395 (NH), 1702 (C=O) cm-'; 'H nmr 6: 1.20-2.52 (m, 9H), 3.02 (m, 3H), 3.51 (broad s, IH), 3.73 (s, 3H), 6.66 (m, 4H); ms m/e: 233 (M', 51), 136 (M' - C6H90, 100). Anal. calcd. for CI4Hl9NO2:C 72.10, H 8.15, N 6.01; found: C 71.86, H 8.23, N 6.11. From lc: the crude product showed three major spots on the tlc plate. They were separated by flash chromatography. First fraction: a white solid melting at 99- 10l°C corresponding to l c (170 mg). Second fraction: a white solid (5c) melting at 82-83OC (88 mg; 6.4%); ir (CHCI,): 1700 (C=O) cm-I; 'H nmr 6: 1.2-2.7 (broad m, 9H), 3.08 (s, 3H), 3.59 (q, AB, 2H), 3.85 (s, 3H), 7.18 (q, 4H); ms m/e: 275 (M', 18), 178 (M' - C6Hy0, 100). Anal. calcd. for C16H21N03: C 69.82, H 7.64, N 5.09; found: C 69.85, H 7.71, N 5.05. Third fraction: an oil (llc) (0.23 g; 16.7%); ir (neat): 1720 (C=O), 1705 (C=O) cm-'; 'H nmr 6: 1.05-2.40 (m, 8H), 2.61 (s, 6H), 3.00 (m, IH), 3.80 (s, 3H), 7.05 (d, lH), 7.80 (d and s, 2H);

molecular weight determination: 273: ms m/e: 275 (M', loo), 260 (M' - CH,, 6). Anal. calcd. for CI6HZINo3: C 69.82, H 7.64, N 5.09; found: 69.90, H 7.75, N 5.15. From Id: the tlc of the crude material showed two major spots which were separated by flash chromatography. First fraction: recovered amine I d (0.21 g). Second fraction: a white solid corresponding to l l d (0.26 g; 20.0%) which melted at 93-94°C after recrystallization from ethanol; ir (CHCI,): 1705 (C=O) 1670 (C=O) cm-'., 1 H nmr 6: 1.50-24.0 (m, 7H), 2.58 (s, 3H), 2.69 (broad s , 7H), 7.28 (m, 2H), 7.90 (m, 2H); ms m/e: 259 (M', loo), 244 (M' - CH,, 31), 216 (M' - CH,CO, 40). Anal. calcd. for C16H21N02: C 74.13, H 8.11, N 5.41; found: C 73.94, H 8.13, N 5.29. From le: practically only polymeric compounds were obtained. A very small quantity of soluble material in ether was isolated and no compound could be obtained pure enough for proper identification. (B) Electrolysis of the amine 1 in the presence of l-pherlyl-ltrimethylsilylo.ry-ethylene 4 From l a : the crude product showed two major and two minor spots on the tlc plate, which were separated by flash chromatography. First fraction: a white solid melting at 56-57OC and corresponding to 8 a (0.57 g; 45.2%); ir (CHCI,): 1680 (C=O) cm-'; I H nmr 6: 2.21 (s, 3H), 2.90 (s, 3H), 3.14 (t, 2H), 3.78 (t, 2H), 6.40-7.92 (m, 9H); ms m/e: 253 (M+, 57). 134 (M+ - C8H70, 100). Anal. calcd. for Cl7HIyNO: C80.63. H7.51, N5.53;found:C80.46, H7.45, N5.60. Second fraction: a white solid melting at 91 -92OC. It analyzed as 9 a (0.17 g; 9.1%); ir (CHCI,): 1680 (C=O) cm-'; 'H nmr 6: 2.21 (s, 3H), 3.16 (t, 4H), 3.86 (t, 4H), 6.40-7.90 (m, 14H); ms m l e : 37 1(M', 14). 252 (M+ - CsH70, 100). Anal. calcd. for CI5H2,NO2: C 80.86, H 6.74, N 3.77; found: C 80.56, H 6.62, N 3.92. The two minor products could not be obtained pure enough for identification. From lb: the crude product was obtained from an ether extraction after addition of water to the reaction mixture. One major and two minor spots showed on the tlc plate. The compounds were separated by flash chromatography. First fraction: a white solid (8b) melting at 57-58°C (0.43 g; 31.9%); ir (CHCI,): 1680 (C=O) cm-I; 'H nmr 6: 2.50-4.10 (m, including the two CH, groups, IOH), 6.41 -7.95 (m, 9H); ms m/e: 269 (M+, 38), 150 (M' - CsH70, 100). Anal. C 75.84, H 7.06, N 5.20; found: C 75.98, calcd. for C17H,yNOZ: H 7.04, N 5.28. Second fraction: a white solid (87 mg) which melted at 99- 100°C after recrystallization from ethanol. The analysis of this solid indicated a mixture of 9b and lob by mass spectrometry. The analysis was done by direct injection and the temperature was programmed from 60-270°C. From lc: water (50 mL) was added to the reaction mixture which was then extracted with ether. The crude product (two important spots on tlc) was purified by a bulb-to-bulb distillation at lo-' Torr. First fraction (60°C): 50 mg of starting amine lc. Second fraction (140°C): an oil corresponding to 8c, which crystallized on standing. It was purified further by recrystallization from ethanol in a Craig tube. A white solid melting at 78-79°C (0.29 g; 19%) was obtained; ir (CHCI,): 1700 (C=O), 1690 (C=O) cm-I; 'H nmr 6: 3.03 (s, 3H), 3.31 (m, 2H), 4.09 (m, including the single of N-CH,), 6.89 (d, 2H), 7.60 (m, 3H), 8.10 (m, 4H); msmle: 297 (M', 21), 178 (M' C 71.58, H 6.67, - C8H70, 100). Anal. calcd. for Cl8HIyNO3: N 4.91; found: C 71.65, H 6.56, N 4.79. A small amount of solid, not very soluble in ether, was also obtained. This compound (9c) melted at 150-151°C after recrystallization from ethanol (78 mg; 3.1%). Anal. calcd. for C26H25N04:C 75.18, H 6.02, N 3.37; found: C 75.06, H 6.24, N 3.41. From Id: the crude product showed two spots on the tlc plate. First fraction from flash chromatrography: the amine I d (66 mg; 8%). Second fraction: a white solid (86) melting at 93-94OC (85 mg; 6%); ir (CHCI,): 1680 (C=O), 1660 (C=O) cm-'; 'H nmr 6: 2.47 (s, 3H), 3.03 (s, 3H), 3.25 (t, 2H), 3.89 (t, 2H), 6.72 (d, 2H), 7.39 (m, 3H), 7.82 (m, 4H); ms m/e: 281 (M', 53), 162 (M' - C n H 7 0 , 100). Anal. calcd. for Cl8HI9NO2:C 76.87, H 6.76, N 4.98; found: C 76.67, H 6.67, N 5.02.

RENAUD ET AL.

From le: to the gummy residue, obtained after the evaporation of the high vapor pressure fraction, was added water (50 mL), and the resulting mixture was extracted with two portions of 50 mL of ether. The crude product gave one major and many minor spots on the tic plate. The major compound was isolated by flash chromatography. A white solid melting at 58-59°C was obtained after recrystallization from ethanol. This compound corresponded to 8e (0.16 g; 13.4%); ir (CHC13): 1678 (C=O) cm-', 'H nmr 6: 2.98 (s, 3H), 3.20 (t, 2H), 3.85 (5, 2H), 6.52-8.00 (m, 10H); ms m l e : 239 (M+, 19), 120 (M+ - C8H70, 100). Anal. calcd. for ClhHI7NO:C 80.33, H 7.11, N 5.86; found: C 80.15, H 7.22, N 5.68.


Acknowledgements W e wish to thank Mr. H . SCguin for the elemental analyses and the molecular weight determination, and Dr. J. L. Holmes of the University of Ottawa for the mass spectral determinations. 1. R . N. RENAUD, D. BERUBE, and C. J. STEPHENS. Can. J. Chem. 61, 1379 (1983).

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2. ( a ) D. M. MOHILNER, R. N . ADAMS,and W. J . ARGERSINGER, JR. J. Am. Chem. Soc. 84,3618 (1962); ( b ) Z. GALUS and R. N. ADAMS.J. Am. Chem. Soc. 84, 1061 (1962); ( c ) Z. GALUS, R. N. WHITE,F. S. ROWLAND, and R. N. ADAMS.J. Am. Chem. SOC.84, 2065 (1962). 3. H. G. VIEHE,R. MERENYI,L. STELLA,and 2 . JANOUSEK. Angew. Chem. Int. Ed. Engl. 18, 917 (1979). J. Chcm. Soc. 1702 4. ( a ) F. P. BOGERTand F. P. NABENHAUER. (1924); ( b ) A. I. VOGEL.A textbook of practical organic chemistry. Longmans, Green and Co., New York. 1956. p. 572; ( c ) H. RlVIER and C. SCHNEIDER. Helv. Chem. Acta, 718 (1919). 5. ( [ I ) R. WEST. J. Org. Chem. 23, 1552 (1958); (b) C. AINSWORTH, F. CHEN,and Y-N. Kuo. J. Organometal Chem. 46, 59 (1972); (c) H. 0. HOUSE,L. J. CZUBA,M. GALL,and H. D. OLMSTEAD. J. Org. Chem. 34, 2324 (1969). 6. G. CAUQUIS,H. F. FAHMY,G . PIERRE, and M. H. ELNAGDI. Electrochim. Acta, 24, 391 (1979). 7. W. C. STILL,M. KAHN,and A. MITRA.J. Org. Chem. 43,2923 (1978).