CRYSTAL GROWTH & DESIGN
Viability of a Covalent Chiral Auxiliary Method to Induce Asymmetric Induction in Solid-State Photoreactions Explored
2005 VOL. 5, NO. 6 2348-2355
Arunkumar Natarajan,† Joel T. Mague,‡ and V. Ramamurthy*,† Departments of Chemistry, University of Miami, Coral Gables, Florida 33124, and Tulane University, New Orleans, Louisiana 70118 Received March 30, 2005
ABSTRACT: The effectiveness of covalent chiral auxiliaries in inducing stereoselectivity during the Yang type II photocyclization reaction was examined using the benzonorbornene phenyl ketone (2) and R-adamantylacetophenone (7) systems. The outstanding ability of covalent chiral auxiliaries in generating high asymmetric induction in the photoproducts has been established in 7 of the 10 investigated examples. Three examples in which molecules crystallize with equal amounts of conformational isomers in the asymmetric unit, despite the covalently linked chiral auxiliary, highlight the limits of the use of the covalent chiral auxiliary approach for asymmetric induction in the solid state. Introduction Controlling the outcome of photochemical reactions is difficult, because of the small activation barriers involved, and has often been attempted through aligning the reactants toward a particular pathway/product. Despite considerable advances through the use of confining media, achieving stereoselectivity in photoreactions still remains a challenging task.1-6 Here too, success has been realized through prealignment of the reactant molecules toward a single stereoisomeric product. For example, in solution the use of templates and covalent chiral auxiliaries has yielded photoproducts with high enantiomeric excess.7-10 In these cases the templates and chiral auxiliaries block one enantiotopic face of the reactants. The best asymmetric induction in photochemical reactions, however, is achieved in the solid state. Schmidt’s group at the Weizmann Institute provided the first example,11 which was achieved by cocrystallizing 1-(2,6-dichlorophenyl)-4-phenyl-trans,trans-1,3-butadiene and the 4-thienyl analogue in a chiral space group. By this process the reactant molecules were biased to yield a single optical isomer of the mixed [2 + 2] photodimer. This ideal approach of obtaining enantiomerically pure photoproduct from achiral reactant molecules most often is unpredictable.12-14 While preorganizing the reactant molecules and restricting their motions in the excited state is the best approach to achieving asymmetric induction in photochemical reactions, reliable strategies are still lacking. Reactant molecules have been forced to crystallize in chiral space groups through the use of chiral host molecules15-17 or through reactant molecules ionically bonded to chiral auxiliaries.18,19 In both cases the photoproducts are easily isolated and analyzed. As one would expect, there are limitations to both approaches, warranting a search for newer methods. In this study we have explored the use of covalent chiral auxiliaries * To whom correspondence should be addressed. E-mail: murthy1@ miami.edu. † University of Miami. ‡ Tulane University.
to achieve asymmetric induction during solid-state photoreaction. To our knowledge there are only three reports of the use of a covalent chiral auxiliary in providing asymmetric induction in the crystalline state.15-17 In all the examples studied the chiral auxiliary is placed at a location remote from the reaction center and is effective only in the solid state. This study highlights the importance of having only one molecule present in the crystallographic asymmetric unit. As expected, there are limitations that are also highlighted in this presentation. Experimental Section Commercial spectral grade solvents were used for photochemical reactions. Melting points were determined using a Mel-Temp apparatus and are uncorrected. Nuclear magnetic resonance spectra were recorded on a 400 MHz (Varian Inova) instrument. Irradiations were performed using a 400 W medium-pressure mercury arc lamp in a water-cooled immersion well. The light emitted from the Hanovia lamp was filtered through Pyrex (transmits λ g290 nm). Gas chromatographic analyses were performed on a Hewlett-Packard 5890 fitted with a flame ionization detector, capillary column RTX5, 15 m × 0.25 mm. High-pressure liquid chromatographic analysis was performed on a Rainin instrument with an HPXL solvent delivery system. For determinations of diastereomeric excesses, chiral columns (Chiralcel OD, OC, OJ; Chiralpak AD, ADRH; 250 mm × 4.6 mm) from Chiral Technologies, Inc., were used. (1) Para-Substituted Amide Derivatives of Benzonorbornene Phenyl Ketone (2). (a) Synthesis. The procedure for the synthesis of compound 1 was kindly provided by Scheffer and Scott.20 Acid 1 (100 mg) was placed in a roundbottom flask and was dissolved in 20 mL of methylene chloride. To this solution was added 1.2 equiv of EDC (1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride), and the solution was stirred for 5 min. At this stage the corresponding optically pure amine or amino acid methyl ester hydrochloride (1.1 equiv) was added and the reaction mixture was stirred for 30 min. The crude product was purified using column chromatography (EtOAc:hexane ) 2:8) to yield amides 2a-e as white solids (in 85-90% yields) (Scheme 1) (b) Characterization. 2a: mp 133-135 °C; 1H NMR (400 MHz, CDCl3; δ, ppm) 1.0-1.05 (dd, 6H, J ) 7.2 Hz), 1.161.18 (d, 2H, J ) 6.8 Hz), 1.99-2.02 (m, 3H), 3.49 (br t, 1H),
10.1021/cg0501175 CCC: $30.25 © 2005 American Chemical Society Published on Web 07/14/2005
Asymmetric Induction in Solid-State Reactions
Crystal Growth & Design, Vol. 5, No. 6, 2005 2349 Scheme 1
Scheme 2
3.64 (br d, 2H), 3.8-3.82 (t, 2H, J ) 4.8 Hz), 3.92-4.0 (m, 1H), 6.34 (d, 1H), 7.11-7.21 (m, 4H), 7.85-7.87 (d, 2H, J ) 8.4 Hz), 7.99-8.01 (d, 2H, J ) 8.4 Hz); GC-MS (EI): 360 (M + 1, 3), 359 (M+, 19), 317 (24), 316 (100), 244 (17), 217 (5), 216 (37), 188 (25), 173 (11), 145 (3), 143 (33), 129 (25), 128 (47), 115 (22), 90 (8). 2b: mp 155-158 °C; 1H NMR (400 MHz, CDCl3; δ, ppm) 1.13-1.8 (m, 15H), 1.64-1.8 (m, 1H), 2.0 (d, 2H), 3.48 (t, 1H), 3.63 (br d, 2H), 3.44-4.04 (m, 1H), 5.95 (d, 1H), 7.1-7.2 (m, 4H), 7.80-7.82 (d, 2H, J ) 8.4 Hz), 7.96-8.0 (d, 2H, J ) 8.4 Hz); GC-MS (EI) 401 (M+, 4), 372 (1), 319 (10), 318 (28), 293 (10), 292 (52), 276 (21), 275 (100), 247 (1), 228 (1), 207 (1), 148 (7), 147 (17), 128 (22), 115 (10), 104 (17), 91 (3). 2c: mp 133-135 °C; 1H NMR (400 MHz, CDCl3; δ, ppm) 1.06-1.1 (d, 2H), 2.0 (d, 2H, J ) 7.2 Hz), 3.31 (s, 3H), 3.47 (t, 1H), 3.52-3.64 (m, 4H), 4.3-4.38 (m, 1H), 5.04-5.08 (d, 1H), 6.83 (d, 1H), 7.07-7.2 (m, 4H), 7.25-7.4 (m, 5H), 7.75-7.77 (d, 2H, J ) 8.4 Hz), 7.95-7.97 (d, 2H, J ) 8.4 Hz); GC-MS (EI) 438 (M + 1, 4), 437 (M+, 7), 393 (30), 392 (100), 364 (1), 331 (4), 300 (15), 292 (14), 275 (7), 253 (3), 221 (3), 207 (23), 172 (4), 129 (13), 128 (20), 119 (90), 91 (57). 2d: mp 148-149 °C; 1H NMR (400 MHz, CDCl3; δ, ppm) 1.15 (d, 2H), 2.0 (d, 2H, J ) 7.2 Hz), 3.0 (d, 2H, J ) 7.2 Hz), 3.47 (t, 1H), 3.63 (br d, 2H), 3.70-3.82 (m, 2H), 4.37-4.39 (m, 1H), 6.40 (d, 1H), 7.13-7.26 (m, 4H), 7.26-7.34 (m, 5H), 7.737.75 (d, 2H, J ) 8.4 Hz), 7.96-7.97 (d, 2H, J ) 8.4 Hz); GCMS (EI) 407 (M+, 1), 317 (22), 316 (100), 288 (1), 264 (4), 173 (5), 145 (11), 143 (19), 129 (17), 128 (14), 115 (10), 91 (10). 2e: mp 160-161 °C; 1H NMR (400 MHz, CDCl3; δ, ppm) 0.97 (d, 3H, J ) 6.4 Hz), 1.15-1.27 (m, 2H), 1.99-2.02 (m, 2H), 2.76 and 3.12 (s, 3H), 3.47-3.49 (d, 1H), 3.64-3.66 (d, 2H), 3.83-3.91 (m, 1H), 4.56 (d, 1H), 4.75 (m, 1H), 7.07-7.22 (m, 4H), 7.27-7.47 (m, 7H), 7.94-7.97 (m, 2H). (2) Compounds 6 and 7. Compound 5 was synthesized by following the reported procedure.21 (a) Synthesis and Characterization of p-Carboxy-1adamantylacetophenone (6). Compound 5 (480 mg, 1.7 mmol) was placed in a 500 mL round-bottom flask, and 25 mL of 25% aqueous NaOH and 50 mL of MeOH were added. The solution was refluxed for 4 h, cooled to room temperature, and acidified with 50% aqueous HCl. The aqueous layer was then
extracted with diethyl ether, and removal of solvent gave a white solid, 6 (470 mg, 1.57 mmol, 92%) (Scheme 2). 6: 1H NMR (400 MHz, CD3OD; δ, ppm) 1.67-1.72 (s, 12H), 1.93 (br s, 3H), 2.8 (s, 2H), 8.03-8.06 (d, 2H), 8.11-8.13 (d, 2H). (b) Synthesis of Para-Substituted Amide and Ester Derivatives of 1-Adamantylacetophenone. Acid 6 (100 mg) was placed in a round-bottom flask and dissolved in 20 mL of methylene chloride. To this solution was added 1.2 equiv of EDC (1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride), and the solution was stirred for 5 min. At this stage the corresponding optically pure alcohol, amine, or amino acid methyl ester hydrochloride (1.1 equiv) was added, and the reaction mixture was stirred for 30 min. The crude product was purified using column chromatography (EtOAc:hexane ) 2:8) to yield compounds 7a-e as white solids (85-90% yields). (c) Characterization. 7a: mp 128-130 °C; 1H NMR (CDCl3, 400 MHz; δ, ppm) 1.22 (d, 3H), 1.54-1.96 (m, 15H), 2.72 (s, 2H), 5.28-5.38 (m, 1H), 6.33 (d, 1H), 7.26-7.4 (m, 5H), 7.82 (d, 2H), 7.96 (d, 2H); GC-MS (EI) 401 (M+, 41), 386 (5), 296 (60), 281 (73), 252 (38), 147 (23), 135 (43), 121 (40), 105 (75), 104 (100), 93 (33), 91 (30), 79 (48). 7b: mp 155-157 °C; 1H NMR (CDCl3, 400 MHz; δ, ppm) 0.948 (t, 3H), 1.5-2.2 (m, 17H), 2.71 (s, 2H), 5.08 (m, 1H), 6.42 (d, 1H), 7.26-7.35 (m, 5H), 7.81 (d, 2H, J ) 8.8 Hz), 7.81 (d, 2H, J ) 8.4 Hz); GC-MS (EI) 415 (M+, 1), 311 (10), 294 (1), 282 (10), 252 (1), 220 (5), 194 (7), 149 (2), 135 (16), 118 (17), 107 (10), 106 (100), 91 (20). 7c: mp 127-129 °C; 1H NMR (CDCl3, 400 MHz; δ, ppm) 0.942-0.971 (m, 6H), 1.18 (d, 3H, J ) 6.8 Hz), 1.22 (m, 1H), 1.53-1.9 (m, 15H), 2.715 (s, 2H), 4.065-4.1 (m, 1H), 5.889 (d, 1H), 7.9 (d, 2H, J ) 7.2 Hz), 7.65 (d, 2H, J ) 7.2 Hz). 7d: mp 135-137 °C; 1H NMR (CDCl3, 400 MHz; δ, ppm) 1.0 (s, 3H), 1.12-1.26 (m, 8H), 1.54-1.7 (s, 14H), 1.78-2.0 (m, 3H), 2.24-2.46 (m, 2H), 2.64-2.72 (m, 1H), 2.73 (s, 2H), 5.25-5.32 (m, 1H), 7.94-7.98 (d, 2H), 7.98-8.11 (d, 2H). 7e: mp 77-80 °C; 1H NMR (CDCl3, 400 MHz; δ, ppm) 1.14 (d, 3H, J ) 6.8 Hz), 1.54 (m, 12H), 1.93 (br s, 3H), 2.4 (m 1H), 2.73 (s, 2H), 3.5 (d, 2H, J ) 5.2 Hz), 4.25-4.36 (m, 2H), 7.97 (d, 2H, J ) 8.0 Hz), 8.1 (d, 2H, J ) 8.0 Hz); GC-MS (EI) 434
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Crystal Growth & Design, Vol. 5, No. 6, 2005
(M + 2, 1), 432 (M+, 1), 416 (1), 297 (9), 285 (7), 283 (8), 254 (20), 253 (100), 211 (2), 149 (11), 135 (13), 104 (7), 93 (6). (3) Solution Photolysis. Ketones 2a-e and 7a-e (5 mg) were dissolved in 10 mL of acetonitrile, and nitrogen was bubbled through the solution for at least 15 min prior to irradiation. Photoproducts were monitored using GC, GC-MS, and TLC. The conversion was kept within 50-60%. (4) Solid-State Photolysis. Crystals of ketones 2a-e and 7a-e (∼2-3 mg) were placed between two Pyrex plates and crushed so as to cover a surface area of 2-3 cm2. The plates were sealed with Parafilm on all sides before the irradiation process. After irradiation the solid was dissolved in an appropriate solvent and the products were analyzed using GC, GC-MS, and TLC. (5) Characterization of Photoproducts. 3a: 1H NMR (400 MHz, CDCl3; δ, ppm) 0.59 (dd, 1H, J ) 11.2 Hz), 1.57 (dd, 1H, J ) 11.2 Hz), 1.03 (dd, 6H, J ) 7.2 Hz), 1.97-1.99 (m, 1H), 2.96 (m, 1H), 3.22 (m, 1H), 3.28-3.30 (m, 1H), 3.83.82 (t, 2H, J ) 4.8 Hz), 3.94-4.0 (m, 1H), 4.26-4.3 (m, 1H), 6.35 (d, 1H), 7.10 (m, 2H), 7.17 (m, 1H), 7.29 (m, 1H), 7.377.4 (m, 2H), 8.02-8.05 (m, 2H). 3b: 1H NMR (400 MHz, CDCl3; δ, ppm): 0.57 (dd, 1H, J ) 11.2 Hz), 1.0-1.82 (m, 15H), 2.96 (m, 1H), 3.15 (br d, 1H), 3.31 (m, 1H), 4.05-4.09 (m, 1H), 4.23 (m, 1H), 5.88 (d, 1H), 7.047.16 (m, 4H), 7.64-7.66 (d, 2H, J ) 7.6 Hz), 7.74-7.76 (d, 2H, J ) 7.6 Hz); GC-MS (EI) 401 (M+, 19), 373 (1), 345 (12), 318 (4), 276 (7), 275 (32), 273 (21), 258 (14), 245 (10), 231 (3), 207 (16), 147 (30), 129 (15), 128 (100), 104 (10), 91 (5). 3c: 1H NMR (400 MHz, CDCl3; δ, ppm) 0.57 (dd, 1H, J ) 11.2 Hz), 1.54-1.56 (dd, 1H, J ) 11.2 Hz), 2.935 (m, 1H), 3.133.16 (m, 1H), 3.28-3.32 (m, 1H), 3.39 (s, 3H), 3.6-3.72 (m, 2H), 4.26 (m, 1H), 4.4-4.43 (m, 1H), 5.12-5.135 (d, 1H), 6.856.87 (d, 1H), 7.05-7.2 (m, 4H), 7.24-7.33 (m, 5H), 7.38-7.4 (d, 2H, J ) 7.6 Hz), 7.96-7.98 (d, 2H, J ) 7.6 Hz); GC-MS (EI) 438 (M + 1, 6), 437 (M+, 20), 393 (16), 392 (55), 381 (11), 346 (3), 331 (3), 300 (16), 292 (16), 281 (26), 264 (21), 275 (3), 253 (6), 221 (4), 219 (6), 208 (12), 207 (60), 172 (8), 147 (17), 129 (27), 128 (71), 119 (100), 91 (84). 3d: 1H NMR (400 MHz, CDCl3; δ, ppm) 0.59 (dd, 1H, J ) 11.2 Hz), 1.57 (dd, 1H, J ) 11.2 Hz), 2.96 (m, 1H), 3.0 (d, 2H, J ) 7.2 Hz), 3.22 (m, 1H), 3.28-3.32 (m, 1H), 3.7-3.82 (m, 2H), 4.3-4.32 (m, 1H), 4.38-4.42 (m, 1H), 6.36 (d, 1H), 7.17.22 (m, 4H), 7.32-7.44 (m, 5H), 7.75-7.77 (d, 2H), 8.2 (d, 2H); GC-MS (EI) 407 (M+, 23), 379 (2), 352 (4), 351 (15), 317 (18), 316 (79), 298 (6), 279 (14), 264 (22), 251 (10), 207 (15), 188 (51), 172(12), 145 (11), 143 (28), 129 (51), 128 (100), 115 (17), 91 (22). 3e: 1H NMR (400 MHz, CDCl3; δ, ppm) 0.57 (dd, 1H, J ) 11.2 Hz), 0.97 (d, 3H, J ) 6.4 Hz), 1.56 (dd, 1H, J ) 11.2 Hz), 2.78 and 3.1 (s, 3H), 2.97 (m, 1H), 3.22 (m, 1H), 3.28-3.32 (m, 1H), 3.83-3.91 (m, 1H), 4.27-4.30 (m, 1H), 4.56 (d, 1H, J ) 8.4 Hz), 7.10 (m, 2H), 7.17 (m, 1H), 7.29-7.54 (m, 8H), 8.028.05 (m, 2H); GC-MS (EI): 421 (M+, 412), 355 (7), 332 (9), 327 (5), 293 (15), 281 (37), 275 (33), 253 (46), 236 (7), 208 (16), 207 (81), 191 (14), 147 (55), 135 (100), 128 (50), 105 (51), 91 (33). 8a: 1H NMR (CDCl3, 400 MHz; δ, ppm) 1.2 (m, 3H), 1.552.3 (m, 14H), 2.6-2.9 (m, 2H), 5.08 (m, 1H), 6.25 (d, 1H), 7.337.35 (m, 5H), 7.375-7.38 (d, 2H, J ) 8.8 Hz), 7.72-7.74 (d, 2H, J ) 8.4 Hz); GC-MS (EI) 401 (M+, 81), 389 (8), 343 (4), 366 (6), 282 (21), 297 (20), 296 (64), 282 (23), 281 (100), 253 (38), 252 (41), 207 (10), 147 (30), 135 (28), 105 (62), 104 (64), 79 (43). 8b: 1H NMR (CDCl3, 400 MHz; δ, ppm) 0.944 (m, 3H), 1.552.3 (m, 16H), 2.6-2.9 (m, 2H), 5.08 (m, 1H), 6.25 (d, 1H), 7.337.35 (m, 5H), 7.375-7.38 (d, 2H, J ) 8.8 Hz), 7.72-7.74 (d, 2H, J ) 8.4 Hz); GC-MS (EI) 415 (M+, 15), 387 (10), 386 (35), 296 (4), 282 (21), 281 (100), 263 (6), 206 (7), 147 (11), 135 (15), 118 (37), 105 (22), 91 (23). 8c: 1H NMR (CDCl3, 400 MHz; δ, ppm) 0.929-0.956 (dd, 6H, J ) 6.8 Hz), 1.16 (d, 3H, J ) 6.8 Hz), 1.54 (d, 11H), 1.72.32 (m, 4H), 2.65-2.9 (m, 2H), 4.04-4.09 (m, 1H), 5.85 (d, 1H), 7.38 (d, 2H, J ) 6.8 Hz), 7.70 (d, 2H, J ) 6.8 Hz). 8d: 1H NMR (CDCl3, 400 MHz; δ, ppm) 1.0 (s, 3H), 1.121.26 (m, 8H), 1.54-1.7 (s, 14H), 1.78-2.4 (m, 5H), 2.64-2.94
Natarajan et al. (m, 2H), 5.25-5.32 (m, 1H), 7.38-7.4 (d, 2H, J ) 8.8 Hz), 8.02 (d, 2H, J ) 8.8 Hz). 8e: 1H NMR (CDCl3, 400 MHz; δ, ppm) 1.12 (d, 3H, J ) 6.8 Hz), 1.57-2.4 (m, 13H), 2.72 (s, 2H), 2.73-2.9 (m, 2H), 3.48 (d, 2H, J ) 5.2 Hz), 4.20-4.32 (m, 2H), 7.4 (d, 2H, J ) 8.0 Hz), 7.9 (d, 2H, J ) 8.0 Hz); GC-MS (EI) 434 (M + 2, 1), 432 (M+, 1), 416 (7), 414 (8), 373 (4), 297 (1), 280 (10), 279 (30), 263 (12), 253 (5), 236 (20), 235 (100), 193 (13), 179 (21), 178 (19), 135 (13), 129 (5), 115 (11). (6) Crystal Structure Determination. Single crystals of compounds 2a,b,d,e and 7a-e were mounted in a Cryoloops with Paratone oil and placed in the cold nitrogen stream of the Kryoflex attachment of a Bruker APEX CCD diffractometer. Full spheres of data were collected using 606 scans in ω (0.3° per scan) at φ ) 0, 120, and 240°. The raw data were reduced to F2 values using the SAINT+ software,22 and a global refinement of unit cell parameters employing approximately 3000-7500 reflections chosen from the full data sets were performed. Multiple measurements of equivalent reflections provided the basis for empirical absorption corrections as well as corrections for any crystal deterioration during the data collection (SADABS23). The structures were solved by direct methods (SHELXS-9724) and completed by successive cycles of full-matrix least-squares refinement followed by calculation of a difference map. All calculations were performed with the SHELXTL25 program package. The crystal structure data of compounds 2a,b,d,e and 7a-e are provided in the Supporting Information and are deposited in the Cambridge Crystallographic Data Centre.
Results With the aim of examining the effectiveness of covalent chiral auxiliaries in providing asymmetric induction during photochemical reactions, we have carried out photochemical and X-ray structural investigations on two systems, namely benzonorbornene phenyl ketone (2)26,27 and adamantyl-1-acetophenone (7).28-30 Upon excitation, these molecules undergo intramolecular hydrogen atom abstraction from their excited triplet states (Schemes 3 and 4). The chiral induction in the Yang photocyclization products was analyzed by HPLC using chiral columns. The chiral auxiliary (esters, amines, amino alcohols, and amino acid methyl esters) was coupled at the para position of the phenyl moiety of the benzoyl group through ester or amide linkages. The behavior of 10 molecules whose crystal structures were determined was compared in both the solution and the solid state. Upon irradiation in solution benzonorbornene phenyl ketones 2a-e abstract one of the two accessible γ-hydrogens from their triplet excited states (Scheme 3). Yang cyclization of the diradicals yields endo-arylcyclobutanols (3a-e) and olefins (4a-e) via a Norrish type II cleavage process (Table 1). Irradiation of substrates (2a-c) in the crystalline state gave the endo-cyclobutanol as the only product at low conversions (Table 1). In the crystalline state the endo isomer was formed with 90% diastereoselectivity (de). This is to be contrasted with the solution irradiation, where the de was less than 2%. However, compounds 2d,e, unlike 2a-c, reacted slowly in the crystalline state, yielding the endocyclobutanols with very low de (80% de) is obtained only when the crystals contain one independent molecule per asymmetric unit. Substrates 2d,e gave very poor diastereoselectivity (
