- Email: [email protected]
Catalytic and photolytic reactions of 5,6,7,8-tetrahydroindolizines with oxygen
Tetrahedron Letters, Vol. 36, No. 38, pp. 6855-6858, 1995 Elsevier Science Ltd Printed in Great Britain 0040-4039/95 $9.50+0.00
Pergamon 0040-4039(95)01437-3
Catalytic and Photolytic Reactions of 5,6,7,8-Tetrahydroindolizines with Oxygen
Ming De Wang and Howard Alper* Department of Chemistry, University of Ottawa, Ottawa, Ontario, Canada K1N 6N5
A b s t r a c t : The C o 2 ( C 0 ) 8 catalyzed reaction of 2-aryl-5,6,7,8tetrahydroindolizines with oxygen gave the corresponding 8ahydroxy-6,7,8,8a-tetrahydro-3(5H)indolizinones in good yield; the same transformation occured by photolysis in the absence of the metal carbonyl.
Transition metal complexes are effective as catalysts for the selective oxidation of organic substrates in combination with oxidizing agents such as hydroperoxides and their derivatives. 1-3 The ability to use molecular oxygen to selectively oxidize organic compounds under mild conditions is an attractive goal, and an extensive search has been made for catalytic systems which will perform such oxidations. One of the more useful classes of catalysts is that based on cobalt salts. 3,4 H e t e r o c y c l i c systems such as furans, oxazoles and i m i d a z o l e s undergo photooxidation reactions to afford useful products. However little use has been made of pyrroles because product yields are low and multiple products are formed along with considerable decomposition. In 1991, elegant work by Wasserman and co-workers 5 revealed that singlet oxygen reacts with 3-methoxy-2carbalkoxypyrroles to form the 2,5-oxygenation product in 45% yield. The yield increased to 80% in the presence of pyridine. In the latter case, irradiation in the presence of a photosensitizer (e.g. methylene blue or rose bengal) is necessary. We now describe our results involving oxygen based catalytic oxidation of 2-aryl5,6,7,8-tetrahydroindolizines to give 2 - a r y i - 8 a - h y d r o x y - 6 , 7 , 8 , 8 a - t e t r a h y d r o - 3 ( 5 H ) indolizinones in 63-76% yield under very mild conditions (1 atm, room temperature). We have recently discovered a new method for synthesizing 5,6,7,8tetrahydroindolizines 2 in good yield by the C o 2 ( C O ) 8 or R u 3 ( C O ) I 2 catalyzed cyclization reaction of 2-methyl(or 2,6-dimethyl)piperidinyl ketones 1. 6
6855
6856
R H
CH3 N
Co2(C0) 8 or -x~v,RU3tOtT~12
:
~
H
o
54 atm CO, C 6 H 6 48h, 200-220°C
Ar
Ar
The ready availability of these systems and the likelihood of enhanced reactivity due to the electron-releasing substituent at the 2-position of 2 has prompted us to explore reactions of 2 with oxygen. When crystals of 2-phenyl5,6,7,8-tetrahydroindolizine (2a, Ar=Ph, R=H) were grown (methylene chloride as solvent) at room temperature over a 4-week period, and a single crystal subjected to X-ray analysis, it was found that the structure was 8a-hydroxy-2-phenyl6,7,8,8a-tetrahydro-3(5H)-indolizinone 3a. 7 The spectral data (e.g. 1H NMR, MS) were also consistent with the structure of 3a.
:~
OH
Ar
2 a, b, c, d,
Ar=Ph, R=H Ar=p-CH3C6H4, R=H Ar=Ph, R=CH 3 Ar=p-CH3C6H4, R=CH 3
O
Ar
3
Ar=Ph, R=H - H20
O
Ph
4
yield (%) a, 63 b, 68 c, 73 d, 76
Compound 3 a , in crystalline form, is stable to air, moisture and light. Dissolution of 3a in a solvent such as CH2C12, CH3OH or CDCI3 and let stand for several months, gave the dehydration product 4a, characterized by 1H NMR, COSY (500MHz) and HMQC (125MHz) spectral data, as well as by elemental analyses. There are no examples, to our knowledge, of 8a-hydroxy-6,7,8,8a-tetrahydro3(5H)indolizinones. Gilbert and Blackburn 8 have developed a synthetic method to prepare alkyl substituted 6,7,8,8a-tetrahydroindolizinones, in 63-70% yield, via N,N-disubstituted-2-oxopropanamides. The transformation of compound 2a to 3a apparently proceeds via C o II catalyzed oxidation by oxygen. When oxygen was bubbled through a mixture of 0.6 mmol of 2a (prepared by Co2(CO)8 catalyzed cyclization reaction of l a ) and 3 mL of
6857
dry, distilled methylene chloride at room temperature for 6h, the conversion of 2 a was 92% (by GC) and the isolated yield of pure 3a was 63%. Similarly reaction of 2(4'-methyl)phenyl-5,6,7,8-tetrahydroindolizine ( 2 b , A r = p - C H 3 C 6 H 4 , R=H) with oxygen and C o 2 ( C O ) 8 g a v e 8 a - h y d r o x y - 2 - ( 4 ' - m e t h y l ) p h e n y l - 6 , 7 , 8 , 8 a - t e t r a h y d r o 3(5H)-indolizinone 3b in 68% yield, and the 5 - m e t h y l - 2 - a r y l - 5 , 6 , 7 , 8 tetrahydroindolizines, i.e. 2c and 2 d , afforded 3c and 3d in 73% and 76% yield, respectively. These results demonstrate that oxygen is the oxidation agent for this transformation. But air, the cheapest oxidant, has rarely been used in the absence of irradiation or without a catalyst. Examples of oxidations by air alone are the conversion of aldehydes into carboxylic acids (autoxidation) and the oxidation of acyloins to a-diketones. 3 Usually, exposure to light, irradiation with ultraviolet light, or catalysts are needed in order to generate oxygen in a reactive state (singlet oxygen). When the reaction of 2a was effected with singlet oxygen generated in situ by irradiation in the presence of rose bengal as a sensitizer (450-W high-pressure mercury immersion lamp with a pyrex filter) 9 for 2 hours, 3 a was isolated in 71% yield. Since the reactants, e.g. 2 a - d , are prepared by a Co2(CO)8 catalyzed cyclization reaction, and then used in the next oxidation reaction, it is possible that a trace amount of oxidized cobalt (II) complexes participated in the oxidation of 2 a - d . In order to check this possibility, the analog of 2 a - d , i.e. 5,6,7,8-tetrahydroindolizine, was prepared following literature methods. 10'11 In this way, the presence of a trace amount of transition metal in the reaction can be avoided. Oxygen was bubbled through a solution of 5,6,7,8-tetrahydroindolizine in C H 2 C 1 2 and the reaction was monitored by GC. After 3 days more than 95% of 5,6,7,8-tetrahydroindolizine was recovered unchanged. H o w e v e r , treatment of 5,6,7,8-tetrahydroindolizine with 3% Co2(CO)8 and 1 atm oxygen for 12h, gave 8ahydroxy-6,7,8,8a-tetrahydro-3(5H)-indolizinone in 32% yield. The photoreaction of 5,6,7,8-tetrahydroindolizine with oxygen in the presence of rose bengal as a sensitizer also afforded 8 a - h y d r o x y - 6 , 7 , 8 , S a - t e t r a h y d r o - 3 ( 5 H ) - i n d o l i z i n o n e (25% yield). Some decomposition and polymerization was observed, during all the oxidation reactions of 5,6,7,8-tetrahydroindolizine, and is probably due to the lack of an electron withdrawing group (e.g. phenyl) at the 2-position which presumably would stabilize a key intermediate. In conclusion, 5,6,7,8-tetrahydroindolizines can be oxidized to form 8ahydroxy-6,7,8,8a-tetrahydro-3(5H)-indolizinones under very mild conditions and in 63-76% yield. These results, together with the previously described cyclization r e a c t i o n , 6 constitutes useful methodology for the synthesis of several types of compounds related to the indolizidine alkaloid skeleton. 12
6858
Acknowledgment: We are grateful to the Natural Research Council of Canada for support of this research.
Sciences
and Engineering
References 1. Katsuki, T.; Sharpless, K.B.J. Am. Chem. Soc., 1980, 102, 5974. 2. (a) Watanabe, Y.; Numada, T.; Oae, S. Synthesis, 1981, 204. (b) Yamaguchi, S.; Inoue, M.; Enomoto, S. Bull. Chem. Soc. Jpn., 1986, 59, 2881. 3. Hudlicky, M. "Oxidation in Organic Chemistry", ACS Monograph 186, Washington, DC, 1990. 4. Li, P.; Alper, H. J. Mol Cat., 1990, 61, 51. 5. Wasserman, H. H.; Frechette, R.; Rotello, V.M.; Schulte, G. Tetrahedron Lett., 1991, 31, 7571. 6. Wang, M.D.; Alper, H. J. Am. Chem. Soc., 1992, 114, 7018. 7. We thank Dr. C. Bensimon for the X-ray structure determination. 8. Gilbert, J.C.; Blackburn, B.K.J. Org. Chem., 1986, 51, 3656. 9. Kaneko, C.; Sugimoto, A.; Tanaka, S. Synthesis, 1974, 876. 10. Carpio, H.; Galeazzi, E.; Greehouse, R.; Guzman, A.; Velarde, E.; Antonio, Y.; Franco, F.; Leon, A.; Perez, V.; Salas, R.; Valdez, D.; Ackrell, J,; Cho, D.; Gallegra, P.; Halpern, O.; Koehler, R.; Maddox, M.L.; Muchowski, J.M.; Prince, A.; Tegg, D.; Thurber, T.C.; Van Horn, A.R.; Wren, D. Can. J. Chem., 1982, 60, 2295. 11. Gmeiner, P.; Lerche, H. Heterocycles, 1990, 31, 9. 12. Barton, D.H.R.; Araujo Pereira, M.M.M.; Taylor, D.K. Tetrahedron Lett., 1994,35, 9157.
(Received in USA 12 July 1995; revised 25 July 1995; accepted 26 July 1995)
Pergamon 0040-4039(95)01437-3
Catalytic and Photolytic Reactions of 5,6,7,8-Tetrahydroindolizines with Oxygen
Ming De Wang and Howard Alper* Department of Chemistry, University of Ottawa, Ottawa, Ontario, Canada K1N 6N5
A b s t r a c t : The C o 2 ( C 0 ) 8 catalyzed reaction of 2-aryl-5,6,7,8tetrahydroindolizines with oxygen gave the corresponding 8ahydroxy-6,7,8,8a-tetrahydro-3(5H)indolizinones in good yield; the same transformation occured by photolysis in the absence of the metal carbonyl.
Transition metal complexes are effective as catalysts for the selective oxidation of organic substrates in combination with oxidizing agents such as hydroperoxides and their derivatives. 1-3 The ability to use molecular oxygen to selectively oxidize organic compounds under mild conditions is an attractive goal, and an extensive search has been made for catalytic systems which will perform such oxidations. One of the more useful classes of catalysts is that based on cobalt salts. 3,4 H e t e r o c y c l i c systems such as furans, oxazoles and i m i d a z o l e s undergo photooxidation reactions to afford useful products. However little use has been made of pyrroles because product yields are low and multiple products are formed along with considerable decomposition. In 1991, elegant work by Wasserman and co-workers 5 revealed that singlet oxygen reacts with 3-methoxy-2carbalkoxypyrroles to form the 2,5-oxygenation product in 45% yield. The yield increased to 80% in the presence of pyridine. In the latter case, irradiation in the presence of a photosensitizer (e.g. methylene blue or rose bengal) is necessary. We now describe our results involving oxygen based catalytic oxidation of 2-aryl5,6,7,8-tetrahydroindolizines to give 2 - a r y i - 8 a - h y d r o x y - 6 , 7 , 8 , 8 a - t e t r a h y d r o - 3 ( 5 H ) indolizinones in 63-76% yield under very mild conditions (1 atm, room temperature). We have recently discovered a new method for synthesizing 5,6,7,8tetrahydroindolizines 2 in good yield by the C o 2 ( C O ) 8 or R u 3 ( C O ) I 2 catalyzed cyclization reaction of 2-methyl(or 2,6-dimethyl)piperidinyl ketones 1. 6
6855
6856
R H
CH3 N
Co2(C0) 8 or -x~v,RU3tOtT~12
:
~
H
o
54 atm CO, C 6 H 6 48h, 200-220°C
Ar
Ar
The ready availability of these systems and the likelihood of enhanced reactivity due to the electron-releasing substituent at the 2-position of 2 has prompted us to explore reactions of 2 with oxygen. When crystals of 2-phenyl5,6,7,8-tetrahydroindolizine (2a, Ar=Ph, R=H) were grown (methylene chloride as solvent) at room temperature over a 4-week period, and a single crystal subjected to X-ray analysis, it was found that the structure was 8a-hydroxy-2-phenyl6,7,8,8a-tetrahydro-3(5H)-indolizinone 3a. 7 The spectral data (e.g. 1H NMR, MS) were also consistent with the structure of 3a.
:~
OH
Ar
2 a, b, c, d,
Ar=Ph, R=H Ar=p-CH3C6H4, R=H Ar=Ph, R=CH 3 Ar=p-CH3C6H4, R=CH 3
O
Ar
3
Ar=Ph, R=H - H20
O
Ph
4
yield (%) a, 63 b, 68 c, 73 d, 76
Compound 3 a , in crystalline form, is stable to air, moisture and light. Dissolution of 3a in a solvent such as CH2C12, CH3OH or CDCI3 and let stand for several months, gave the dehydration product 4a, characterized by 1H NMR, COSY (500MHz) and HMQC (125MHz) spectral data, as well as by elemental analyses. There are no examples, to our knowledge, of 8a-hydroxy-6,7,8,8a-tetrahydro3(5H)indolizinones. Gilbert and Blackburn 8 have developed a synthetic method to prepare alkyl substituted 6,7,8,8a-tetrahydroindolizinones, in 63-70% yield, via N,N-disubstituted-2-oxopropanamides. The transformation of compound 2a to 3a apparently proceeds via C o II catalyzed oxidation by oxygen. When oxygen was bubbled through a mixture of 0.6 mmol of 2a (prepared by Co2(CO)8 catalyzed cyclization reaction of l a ) and 3 mL of
6857
dry, distilled methylene chloride at room temperature for 6h, the conversion of 2 a was 92% (by GC) and the isolated yield of pure 3a was 63%. Similarly reaction of 2(4'-methyl)phenyl-5,6,7,8-tetrahydroindolizine ( 2 b , A r = p - C H 3 C 6 H 4 , R=H) with oxygen and C o 2 ( C O ) 8 g a v e 8 a - h y d r o x y - 2 - ( 4 ' - m e t h y l ) p h e n y l - 6 , 7 , 8 , 8 a - t e t r a h y d r o 3(5H)-indolizinone 3b in 68% yield, and the 5 - m e t h y l - 2 - a r y l - 5 , 6 , 7 , 8 tetrahydroindolizines, i.e. 2c and 2 d , afforded 3c and 3d in 73% and 76% yield, respectively. These results demonstrate that oxygen is the oxidation agent for this transformation. But air, the cheapest oxidant, has rarely been used in the absence of irradiation or without a catalyst. Examples of oxidations by air alone are the conversion of aldehydes into carboxylic acids (autoxidation) and the oxidation of acyloins to a-diketones. 3 Usually, exposure to light, irradiation with ultraviolet light, or catalysts are needed in order to generate oxygen in a reactive state (singlet oxygen). When the reaction of 2a was effected with singlet oxygen generated in situ by irradiation in the presence of rose bengal as a sensitizer (450-W high-pressure mercury immersion lamp with a pyrex filter) 9 for 2 hours, 3 a was isolated in 71% yield. Since the reactants, e.g. 2 a - d , are prepared by a Co2(CO)8 catalyzed cyclization reaction, and then used in the next oxidation reaction, it is possible that a trace amount of oxidized cobalt (II) complexes participated in the oxidation of 2 a - d . In order to check this possibility, the analog of 2 a - d , i.e. 5,6,7,8-tetrahydroindolizine, was prepared following literature methods. 10'11 In this way, the presence of a trace amount of transition metal in the reaction can be avoided. Oxygen was bubbled through a solution of 5,6,7,8-tetrahydroindolizine in C H 2 C 1 2 and the reaction was monitored by GC. After 3 days more than 95% of 5,6,7,8-tetrahydroindolizine was recovered unchanged. H o w e v e r , treatment of 5,6,7,8-tetrahydroindolizine with 3% Co2(CO)8 and 1 atm oxygen for 12h, gave 8ahydroxy-6,7,8,8a-tetrahydro-3(5H)-indolizinone in 32% yield. The photoreaction of 5,6,7,8-tetrahydroindolizine with oxygen in the presence of rose bengal as a sensitizer also afforded 8 a - h y d r o x y - 6 , 7 , 8 , S a - t e t r a h y d r o - 3 ( 5 H ) - i n d o l i z i n o n e (25% yield). Some decomposition and polymerization was observed, during all the oxidation reactions of 5,6,7,8-tetrahydroindolizine, and is probably due to the lack of an electron withdrawing group (e.g. phenyl) at the 2-position which presumably would stabilize a key intermediate. In conclusion, 5,6,7,8-tetrahydroindolizines can be oxidized to form 8ahydroxy-6,7,8,8a-tetrahydro-3(5H)-indolizinones under very mild conditions and in 63-76% yield. These results, together with the previously described cyclization r e a c t i o n , 6 constitutes useful methodology for the synthesis of several types of compounds related to the indolizidine alkaloid skeleton. 12
6858
Acknowledgment: We are grateful to the Natural Research Council of Canada for support of this research.
Sciences
and Engineering
References 1. Katsuki, T.; Sharpless, K.B.J. Am. Chem. Soc., 1980, 102, 5974. 2. (a) Watanabe, Y.; Numada, T.; Oae, S. Synthesis, 1981, 204. (b) Yamaguchi, S.; Inoue, M.; Enomoto, S. Bull. Chem. Soc. Jpn., 1986, 59, 2881. 3. Hudlicky, M. "Oxidation in Organic Chemistry", ACS Monograph 186, Washington, DC, 1990. 4. Li, P.; Alper, H. J. Mol Cat., 1990, 61, 51. 5. Wasserman, H. H.; Frechette, R.; Rotello, V.M.; Schulte, G. Tetrahedron Lett., 1991, 31, 7571. 6. Wang, M.D.; Alper, H. J. Am. Chem. Soc., 1992, 114, 7018. 7. We thank Dr. C. Bensimon for the X-ray structure determination. 8. Gilbert, J.C.; Blackburn, B.K.J. Org. Chem., 1986, 51, 3656. 9. Kaneko, C.; Sugimoto, A.; Tanaka, S. Synthesis, 1974, 876. 10. Carpio, H.; Galeazzi, E.; Greehouse, R.; Guzman, A.; Velarde, E.; Antonio, Y.; Franco, F.; Leon, A.; Perez, V.; Salas, R.; Valdez, D.; Ackrell, J,; Cho, D.; Gallegra, P.; Halpern, O.; Koehler, R.; Maddox, M.L.; Muchowski, J.M.; Prince, A.; Tegg, D.; Thurber, T.C.; Van Horn, A.R.; Wren, D. Can. J. Chem., 1982, 60, 2295. 11. Gmeiner, P.; Lerche, H. Heterocycles, 1990, 31, 9. 12. Barton, D.H.R.; Araujo Pereira, M.M.M.; Taylor, D.K. Tetrahedron Lett., 1994,35, 9157.
(Received in USA 12 July 1995; revised 25 July 1995; accepted 26 July 1995)