J. Am. Chem. SOC.1992, 114, 1812-1816
1812
off-whiteoily solid (88%). Distillation of the acid gave a colorless liquid (128 mg; 77%): [aID= +17.7 (c 2.37, EtOH) [aID= +17.87 (c 5.30, EtOH)]; 'H NMR 6 1.22 (d, J = 6.9 Hz, 3 H, CH3CHCOOH), 2.67-2.86 (m, 2 H, C,H,CH2), 7.23-7.35 (m, 5 H, aromatic), 11.08 (br s, 1 H, COOH); "C NMR6 16.6, 39.4, 41.4, 126.5, 128.5, 129.1, 139.2, 182.9; IR (thin film) 3400, 1703 cm-l. HRMS (EI) calcd for CIOH1202: 164.08376. Found: 164.08382. (b) Heterocycle 39 (100 mg, 0.331 mmol) was deacylated under conditions identical to those described above for 36. TLC showed the reaction to be complete in 30 min, and methyl chloroformate (28 pL, 0.36 mmol) was added; the resulting mixture was allowed to stir at room temperature for 4 h. Workup as described for 36 preceded drying of the organic layer (MgSOJ, filtration, and evaporation of solvent to afford 1 (530 mg, 76%). The aqueous layer was acidified with HCI and extracted with CH2CI2.Drying of the organic layer (MgS04),filtration, and evaporation of solvent gave 37 (48 mg, 85%).
Institutes of Health (GM 45015), and the donors of The Petroleum Research Fund, administered by the American Chemical Society, is gratefully acknowledged. In addition, it is a pleasure to extend our heartfelt thanks to Professors D. Seebach (ETH) and E. Juaristi (Mexico) for sharing their research results prior to publication, to Professors W. H. Okamura, M. M. Midland, S. R. Angle, J. M. Nuss (UC Riverside), and L. S. Hegedus (Colorado State) for very helpful discussions concerning the palladium-catalyzed reactions of 1, and to Professor P. DeShong (Maryland) for the MM2 calculations on 24 and 25. Finally, G.R.N. is thankful to the University of California for a Mentorship Award and a Dissertation Year Fellowship, as well as the NIH for Minority Biomedical Research Support and a Patricia Roberts Harris Fellowship.
Acknowledgment. Research support by the U C Santa Cruz Committee on Research, American Cancer Society, the National
Supplementary Material Available: Crystallographic data for 1 and 11 (14 pages). Ordering information is given on any current masthead page.
Triethylamine-Photosensitized Reduction of a Ketone via a Chemical Sensitization Mechanism' Zheng-Zhi Wu,+ Gordon L. Hug,* and Harry Morrison*,+ Contribution from the Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, and the Radiation Laboratory, University of Notre Dame, Notre Dame, Indiana 46556. Received May 30, 1991. Revised Manuscript Received August 29, 1991
Abstract: Photolysis of acetonitrile solutions of 30-hydroxy-Sa-androstan-1 'I-one (l),or its 3P-methoxy analogue (5), and triethylamine (TEA) with 254-nm light leads to reduction of the 17-keto group with high stereoselectivity. By contrast, Norrish type I products are exclusively observed when the photolysis is carried out in cyclohexane, and products from both a-cleavage and reduction are observed in ether or THF. Excitation of TEA in acetonitrile results in the photoionization of the amine to form a radical cation and a solvent radical anion. Several possible mechanisms for reduction of ground-state ketones by these species, or radicals derived therefrom, are outlined. The limiting quantum efficiency for reduction of 1is 0.17. The results observed in cyclohexane are explained by singletsinglet energy transfer from the TEA excited state to the ketone, while both photoionization and energy transfer appear to be operating in the ethereal solvents.
-
The photoreduction of aromatic ketones by aliphatic amines Scheme I. Mechanism for Reduction of a Ketone Excited State by an Amine has been a subject of extensive investigation.24 Early studies by Cohen and c o - w o r k e r ~ , ~as- ~well as more recent studies,8-l' Ar,C=O*Cr,) + CH3CH,NEt, [Ar,C-6 CH,Cykt,] have demonstrated that a radical ion pair is generated through electron transfer from the ground-state amine to the photoexcited A r l C = O ( S o ) + C H ~ C H I N E ~ IL r , t - o H + C Y h i E t , ketone, followed by proton transfer from the amine radical cation to the ketyl species (Scheme I). Tertiary amines, such as tridiated with 2 5 4 - m light, Using a Ca. 10:1 ratio Of amine to ketone ethylamine (TEA), have frequently been used in these reacsuch that the TEA absorbs 99% of the incident one obtains tions. I 2 ~ 1 However, amines are themselves readily excited in the near UV, and although the photophysics of aliphatic amines has been (1) Morrison, H.; Olack, G.; Xiao, C. Organic Photochemistry. Part 94. thoroughly investigated,l4-I6 very little attention has been paid Part 93. J . Am. Chem. SOC.1991, 113, 811C-8118. (2) Cohen, S. G.; Parola, A,; Parsons, G. H., Jr. Chem. Rev. 1973, 73, to the photochemical consequences of amine excitation in the 141-161. presence of other functionalities, such as ketone^.'^,'^ We now (3) Wagner, P. Top. Curr. Chem. 1976, 66,1-53. report a new mechanism for the photoreduction of ketones in(4) Kavarnos, G. J.; Turro, N. J. Chem. Rev. 1986, 86,428-437. volving photoexcitation of an amine followed by ionization of the ( 5 ) Cohen, S. G.; Chao, H. M. J. Am. Chem. SOC.1968, 90, 165-173. (6) Cohen, S. G.; Stein, N. J . Am. Chem. SOC.1969, 91, 3690-3691. amine (Le., for triethylamine: formation of TEA'+). Photoinduced (7) Inbar, S.; Linschitz, H.; Cohen, S. G. J . Am. Chem. SOC.1981, 103, reductions wherein the target functionality reacts through 1048-1054. ground-state chemistry have been referred to as proceeding (8) Peters, K. S.; Freilich, S. C.; Schaeffer, C. G. J. Am. Chem. Soc. 1980, through "chemical ~ e n s i t i z a t i o n " ,as~ ~exemplified ~~~ by the ben102, 5701-5702. zophenone-sensitized photoreduction of aryl-N-alkylimine~,'~,~~~ (9) Simon, J. D.; Peters, K. S. J . Am. Chem. SOC.1981,103,6403-6406. (10) Schanze, K. S.; Lee, L. Y. C.; Giannotti, C.; Whitten, D. G. J. Am. dibenzoylethylene,21band acridine.21c Chem. SOC.1986, 108,2646-2655. (1 1) Setsune, J.; Fujiwara, T.; Murakami, K.; Mizuta, Y.; Kitao, T. Chem. Results and Discussion Left. 1986, 1393-1396. Photoreduction of Steroidal Ketones via Excitation of TEA. (12) For example, see: (a) Ci, X.; Silveira da Silva, R.; Nicodem, D.; When 38-hydroxy-Sa-androstan-17-one (1) and TEA are irraWhitten, D. G. J . Am. Chem. Soc. 1989, 111, 1337-1343. (b) Ci, X.; da Silva, R. S.; Goodman, J. L.; Nicodem, D. E.; Whitten, D. G. J . Am. Chem. SOC. 'Purdue University. 'University of Notre Dame.
4
1988,110,8548-8550. (c) For an example involving conjugated ketones, see: Schuster, D. V.;Insogna, A. M. J. Org. Chem. 1991, 56, 1879-1882.
0002-7863/92/1514-1812$03.00/0
0 1992 American Chemical Society
TEA- Photosensitized Reduction of a Ketone
J . Am. Chem. Soc., Vol. 114, No. 5, 1992 1813
Table I. Solvent Effects on Photoreactions of the Ketone 1 Initiated
Table 11. Solvent Effects on Photoreactions of the Ketone 1 under
by Photoexcitation of TEA"
Photoexcitation of 1'
yield,b % ratio loss solvent 2 3 4 2/(3 of 1, % , . + 4) cyclohexaned*c c 45.6 6.3 70.4 Et20d 6.8 60.4 23.1 0.081 78.7 THFd 14.5 35.9 5.4 0.35 76.8 MeCN 79.0 2.2 c 74.7 'Photoreactions were conducted on solutions of [ 11 = 13.9 mM and [TEA] = 145 mM with 254-nm light at 28 OC for 20 min. bYields were determined by GLC analysis relative to an internal standard and are based on recovered starting ketone. CNonedetectable. dAn unknown (4-12%) was also detected with a long GLC retention time. c [ l ] = 7.7 mM; [TEA] = 72.5 mM.
yield,b*c% ratio loss 2 3 4 314 of 1. % 2.4 45.2 11.4 4.0 26.2 (3.3) (43.8) (0) (44.6) (13.7) THF 2.0 77.3 18.3 4.2 27.0 (3.8) (44.0) (0) (72.2) (18.8) MeCN 2.0 74.0 16.4 4.5 29.1 (3.7) (51.5) (0) (65.4) (17.5) 'Photoreactions were conducted on solutions of [ l ] = 55 mM and [TEA] = 361 mM with 300-nm light at 28-32 OC for 25 min. bYields were determined by GLC analysis relative to an internal standard and are based on recovered starting ketone. cThe data in parentheses are in the absence of TEA. solvent Et20
products resulting from Norrish type I a-cleavage (3, 4)23,24 and/or the alcohol (2) resulting from ketone redu~tion:~with the product ratio strongly dependent on the solvent (eq 1). Thus, photolysis
1 16.0
I
2
t
~
4
3
&oo
HO 4
in degassed acetonitrile overwhelmingly generates 5aandrostane-3j3,17P-diol (2),25whereas photolysis in cyclohexane exclusively generates the epimer, 3j3-hydroxy-5a, 13a-androstan17-one (3), and the aldehyde [3@-hydroxy-13,17-seco-5aandrost- 13-en-17-aldehyde (4)]. Photolysis in ether or THF gives both a-cleavage and reduction products. A particularly interesting point is that adding 10%water into acetonitrile solution completely quenches photoreduction and initiates a-cleavage of the ketone 1, although the loss of 1 is very low with respect to other solvent systems over the same time period of irradiation. The data for various solvent systems are summarized in Table I. The methylated ketone, 38-methoxy-5a-androstan- 17-one (9, shows similar photochemical behavior to its alcohol precursor.
1
8.01
I
I
20.0
references cited therein. (20) Fischer, M. Tetrahedron Lett. 1966,5273-5277. Fischer, M. Chem.
Ber. 1967, 100, 3599-3608. (21) (a) Padwa, A.; Bergmark, W.; Pashayan, D. J . Am. Chem. Soc. 1969, 91,2653-2660. (b) Zimmerman, H. E.; Hull, V. J. J. Am. Chem. SOC.1970, 92, 6515-6520. (c) Donckt, E. V.; Porter, G. J . Chem. Phys. 1967, 46, 1173-1175. (22) In acetonitrile at 254 nm, €(TEA) = 47 M-' cm-' and c(1) = 6 M-I
cm-I.
(23) For a review of Norrish type I cleavage, see: Weiss, D. S. Org. Photochem. 1981, 5 , 347-420. (24) For analogouschemistry in related steroids, see: Wu, Z. Z.; Morrison, H. J. Am. Chem. SOC.1989, 111, 9267-9269. Wu, Z. Z.; Morrison, H. Tetrahedron Lett. 1990, 5865-5868. (25) This reaction proceeds with rather high efficiency and sterecselectivity
and may prove to be a useful synthetic methodology for the reduction of cycloalkanones. Extended irradiation times (75 min) gave a small amount (5) (ratio of 2 5 = 15.2:l.O). of the 17a-isomer, 5a-androstane-3/3,17a-diol
,
I
I
I
,
I
I
,
,
80.0
60.0
40.0
lAll (IM)
Figure 1. Stern-Volmer plot for reduction of 1 initiated by photoexci-
tation of TEA in acetonitrile at room temperature.
Thus, photoexcitation of TEA in acetonitrile at 254 nm initiates reduction of 5 to form 38-methoxy-5a-androstan-178-01 (6, eq 2).
& 4: TEA-MeCN hvD54nm,
Me0
Me0
(13) Ci, X.; Whitten, D. G. In Photoinduced Electron Transfer; Fox, M. A., Chanon, M., Ws.;Elsevier Science Publishers: New York, 1988; Chapter 4.9, pp 553-577, and references cited therein. (14) Muto, Y.; Nakato, Y.; Tsubomura, H. Chem. Phys. Lett. 1971, 9, 597-599. (15) Halpern, A. M. In Chemistry of Amino, Nitroso, and Nitro Compounds and Their Derivatives; Patai, S., Ed.; Wiley: New York, 1982; Vol. 1 , pp 155-180 and earlier papers cited therein. (16) Beecroft, R. A.; Davidson, R. S. J. Chem. Soc., Perkin Trans. 2 1985, 1063-1067. (17) Halpern, A. M.; Lyons, A. L., Jr. J. Am. Chem. SOC.1975, 98, 3242-3247. (18) We suspect that another example may be found in: Belotti, D.; Cossy, J.; Pete, J. P.; Portella, C. Tetrahedron Lett. 1985, 26, 4591-4594. (19) Padwa, A.; Koehn, W. P. J . Org. Chem. 1975,40, 1896-1902, and
I
6
(2)
lace
By contrast with the above, direct excitation of the ketone 1 with 300-nm light in the presence of TEA does not afford much reduction or demonstrate significant solvent-dependent photochemical behavior. Irradiation of 1 (55 mM) and TEA (360 mM) in acetonitrile, THF, or ether gives predominantly the a-cleavage products, 3 (yield, ca. 45-77%) and 4 (ca. 11-18%), as well as a small amount of the reduction product 2 (ca. 2%). These results are not much different from those one observes in the absence of TEA, wherein photolysis in each of the three solvents generates only the a-cleavage products,26with a ratio for 3 to 4 of 3.3-3.8, slightly less than in the presence of TEA (4.0-4.5). These results confirm that the singlet excited state of 1 reacts primarily through rapid singlet-state-derived a-cleavage rather than intersystem crossing to the triplet where reduction by the amine could be anticipated. The data in the presence and absence of TEA are summarized in Table 11. The source of the hydrogens involved in the reduction of the ketones was explored by photolysis of 5 and TEA in CD3CN using 254-nm excitation. The reaction gives a GLC trace identical to that observed in CH3CN. Mass spectral analysis of the reduction product (6) generated in the CD3CN shows ca. 5% deuterium incorporation. ~
~
~~~
~
~~
(26) Wehrli, A,; Schaffner, K. Helv. Chim Acta 1962, 45, 385-389. Schaffner, K.; Jeger, 0 Tetrnhedron 1974, 30, 1891-1902, and references
cited therein.
Wu et al.
1814 J. Am. Chem. Soc., Vol. 114, No. 5, 1992
Scheme 11. Possible Chemical Sensitization Mechanisms for Reduction of a Ketone upon Photoexcitation of Triethylamine
50
CH,CH~NEI;
40
l0-I
CH,CN
I
I
CH,CH,F~EI~ I
+
(CH,CN
