Synthesis and Conformational Dynamics of Tricyclic Pyridones

Austin J. Reeve, Michael Rowley, Alan Nadin, and Andrew P. Owens ... The Neuroscience Research Centre, Terlings Park, Harlow, Essex CM20 2QR, UK...
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Synthesis and Conformational Dynamics of Tricyclic Pyridones Containing a Fused Seven-Membered Ring Karl R. Gibson,† Laure Hitzel,† Russell J. Mortishire-Smith,* Ute Gerhard, Richard A. Jelley, Austin J. Reeve, Michael Rowley, Alan Nadin, and Andrew P. Owens Medicinal Chemistry Department, Merck Sharp & Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Harlow, Essex CM20 2QR, UK [email protected] Received September 6, 2002

A new synthetic approach to tricyclic pyridones bearing a fused seven-membered ring is described. These compounds exhibit atropisomerism and exist in enantiomeric forms. Chiral HPLC separation of the enantiomers has allowed the rates of racemization to be measured and hence the free energy barrier for flipping the seven-membered ring to be deduced. Introduction of a further element of planar chirality leads to diastereomeric atropisomerism. The rate of interconversion of the diastereomers has been quantified by 2D EXSY NMR spectroscopy allowing a full description of the conformational dynamics of the system. Introduction As part of our ongoing studies into the use of highly substituted pyridones as novel anxiolytic agents,1-5 we chose to examine the conformational dynamics of a class of compounds represented by 1, containing a fused sevenmembered ring as part of the tricyclic scaffold. To the best of our knowledge there has been little study of the conformational properties of such complex heteroaromatic molecules. Compound 1 possesses a tri-orthosubstituted biaryl bond between the pyridone and pyridine rings. Hence, 1 has the potential to exhibit atropisomerism. Compounds such as 1 were originally synthesized by a radical-mediated seven-membered-ring closure, followed by installation of the C5-substituent by a palladium(0)-mediated cross-coupling reaction.1 An alternative, complementary synthesis in which the C3substituent is introduced late-on and which avoided the use of toxic organo-tin reagents was sought in order to facilitate access to this class of compounds.6 Results and Discussion Synthesis. Retrosynthetic analysis (Scheme 1) suggested that the seven-membered ring could be closed via an intramolecular alkylation of the pyridone, and that * Address correspondence to this author. † The contribution of these two authors was equivalent. (1) Nadin, A.; Harrison, T. Tetrahedron Lett. 1999, 40, 4073. (2) Harrison, T.; Moyes, C. R.; Nadin, A.; Owens, A. P.; Lewis, R. T. WO 98/50384, Merck Sharp & Dohme Ltd., UK. (3) Fischer, U.; Moehler, H.; Schneider, F.; Widmer, U. Helv. Chim. Acta 1990, 73, 763. (4) (a) Burner, S.; Canesso, R.; Widmer, U. Heterocycles 1994, 37, 239. (b) Spurr, P. R. Tetrahedron Lett. 1995, 36, 2745. (5) Collins, I.; Moyes, C.; Davey, W. B.; Rowley, M.; Bromidge, F. A.; Quirk, K.; Atack, J. R.; McKernan, R. M.; Thompson, S.-A.; Wafford, K.; Dawson, G. R.; Pike, A.; Sohal, B.; Tsou, N. N.; Ball, R. G.; Castro, J. L. J. Med. Chem. 2002, 45, 1887. (6) The biological properties of these compounds and related analogues will be reported in due course.

SCHEME 1.

Retrosynthetic Analysis of 1

the pyridone could be formed from the cyclocondensation of heteroarylacetamide 2, ketone 3, and a DMF equivalent.7 It was envisaged that 3 could be accessed from an aryl acetic acid, of which many are commercially available, and substituted nicotinic acid 4. The success of the synthetic strategy is illustrated by the syntheses of the tricyclic pyridones 5a and 5b described in Scheme 2. Commercially available 3-bromo4-methylpyridine was converted to alcohol 6 under literature conditions.1,8 The alcohol was protected as the silyl ether 7 and a palladium-mediated carbonylation provided methyl ester 8 which was hydrolyzed to give (7) For reviews of this and similar routes to 2-pyridones see: (a) Jones, G. In Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford, UK, 1996; Vol. 5, pp 167-243. (b) Jones, G. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon: Oxford, UK, 1984; Vol. 2, pp 395-510. (8) Bracher, F.; Mink, K. Liebigs Ann. 1995, 645. 10.1021/jo026411a CCC: $22.00 © 2002 American Chemical Society

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Tricyclic Pyridones Containing a Fused Seven-Membered Ring SCHEME 2.

Syntheses of 5a and 5ba

1 H NMR spectra (500 MHz) of 14 in d6-DMSO acquired from 300 to 373 K.

FIGURE 1.

FIGURE 2. Atropisomers of 14.

Reagents and conditions: (a) LDA, ethylene oxide, THF, -20 °C. (b) TBDMSCl, imidazole, CH2Cl2, rt. (c) Pd(OAc)2, Ph2P(CH2)3PPh2, EtNiPr2, CO, MeOH, DMF, 95 °C. (d) KOTMS, Et2O, rt; then citric acid. (e) CDI, DMF, 50 °C; then ArCH2CO2Me, NaH, 0 °C to rt. (f) NaCl, H2O, DMSO, 150 °C. (g) DMF-DMA, rt. (h) 2, HaH, DMF, 50 °C; then HCl. (i) DEAD or DIAD, PPh3, THF, rt. a

the desired nicotinic acid 9 in good yield. Activation as the imidazolide followed by a Claisen condensation with either methyl phenylacetate or methyl o-tolylacetate gave the β-ketoesters 10. Decarboxylation under Krapcho’s9 conditions gave ketones 11. Treatment with dimethylformamide-dimethyl acetal gave the corresponding dimethylaminopropen-2-ones 12; these intermediates were not purified and underwent a base-mediated condensation with thiazole acetamide 2,10 forming the pyridone ring via a modification of Lesher’s method.11,12 As precedented in the literature the cyclization installed the pyridone ring system regioselectively with the thiazole para to the pyridyl group.5,13-15 The silyl ethers were cleaved by treatment with acid on workup producing (9) Krapcho, A. P.; Lovey, A. J. Tetrahedron Lett. 1973, 14, 957. (10) Domasevich, K. V.; Mokhir, A. A.; Krugylak, D. M.; Yudin, E. K. Zh. Obshch. Khim. 1995, 65, 1031. Now commercially available from Maybridge Chemical Company. (11) Lesher, G. Y.; Philion, R. E. U.S. Patent 4 313 951, February 2, 1982. (12) Lesher, G. Y.; Gruett, M. D. U.S. Patent 4 264 612, April 28, 1981. (13) Only the regioisomer with the thiazole para to the pyridyl group was detected. Assignment of the regiochemistry is based on the observation that the subsequent seven-membered-ring cyclization occurs. (14) Robertson, D. W.; Beedle, E. E.; Swartzendruber, J. K.; Jones, N. D.; Elzey, T. K.; Kauffman, R. F.; Wilson, H.; Hayes, J. S. J. Med. Chem. 1986, 29, 635.

alcohols 13 in good yield from the ketones 11. Activation of the alcohol under Mitsunobu conditions effected closure of the seven-membered ring to give the tricyclic pyridones 5 in high yield in a fast and clean reaction. In summary, this complex, highly substituted class of molecules can be synthesized in good yields in just 8 steps from commercially available 3-bromo-4-methylpyridine. Conformational Behavior of Tricyclic Pyridones. The synthesis of the unsubstituted pyridone 14 has been previously described.1 Figure 1 shows the 1H NMR spectra of this compound in d6-DMSO over a range of temperatures. The starred resonances can be assigned to the methylene of the seven-membered ring adjacent to nitrogen. These protons are nonequivalent at 300 K, which is consistent with the presence of a chiral element in the molecule on the NMR time scale. We assume that hindered rotation about the pyridone-pyridine bond allows the molecule to exist as a pair of enantiomeric atropisomers (Figure 2), where flipping the sevenmembered ring inverts the stereochemistry. The rate of interconversion when the two resonances coalesce in the NMR spectrum can be approximated using the expression

kc ) 2.22∆ν where ∆ν is the chemical shift difference in hertz of the two exchanging protons when in slow exchange.16 Inspection of the variable-temperature series indicates a coalescence temperature (Tc) of 323 K for 14, yielding an (15) Sircar, I.; Duell, B. L.; Bristol, J. A.; Weishaar, R. E.; Evans, D. B. J. Med. Chem. 1987, 30, 1023. (16) Gutowsky, H. S.; Holm. C. H. J. Chem. Phys. 1956, 25, 1228.

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FIGURE 3.

1

H NMR of 5a (500 MHz, CDCl3).

exchange rate of 400 s-1. This corresponds to a free energy barrier for flipping the seven-memberd ring of ∆Gq ) 63 kJ mol-1 at 323 K. This compares to the measured free energy for 6,7-dihydro-5H-dibenzo[a,c]cycloheptene (15) of ∆Gq ) 52 kJ mol-1 at 294 K.17

FIGURE 4. Interconversion of atropisomers of 5a monitored by chiral HPLC.

O h ki defines atropisomerism as a type of conformational (rotational) isomerism in which the conformational isomers can be isolated and have a half-life of at least 1000 s.18 Clearly compound 14 does not satisfy these conditions. However, spectral and chromatographic properties of C5-substituted compounds in this series (such as 5a and 5b) suggested that they existed formally as mixtures of atropisomers and we undertook further evaluation of these compounds. Conformational behavior of 5a. In the 1H NMR spectra of 5a (Figure 3) a single species is present; however, the alkyl protons of the seven-membered ring are once again nonequivalent. The relative sharpness of the NMR spectrum compared with that observed for 14 is consistent with substantially slower interconversion between the enantiomeric conformers. High-temperature NMR experiments failed to give coalescence. However, using a chiral stationary phase, we were able to resolve the two forms by HPLC and hence measure their rates of interconversion. Rate of Interconversion of Atropisomers of 5a Using Chiral HPLC. Upon injection of 5a onto an appropriate chiral HPLC column, two peaks of equal area are observed. A slightly raised baseline is observed between the peaks, consistent with interconversion of species on the column. The peaks were collected separately and then the rate of racemization followed by sequential reinjection of each peak, monitoring the reappearance of the other peak (Figure 4). The half-life of racemization of 5a was determined to be 33.0 and 30.5 min for each of its enantiomers giving (17) Mu¨llen, K.; Heinz, W.; Klaemer, F. G.; Roth, W. R.; Kindermann, I.; Adamczak, O.; Wette, M.; Lex, J. Chem. Ber. 1990, 123, 2349. (18) O h ki, M. Top. Stereochem. 1983, 14, 1.

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FIGURE 5. Racemization of 5a at 293 K.

rate constants for the interconversion of 1.75 × 10-4 and 1.89 × 10-4 s-1 thus satisfying the definition of atropisomers given by O h ki. The rates of racemization correspond to an average free energy barrier for interconverting the enantiomers of ∆Gq ) 92.7 ( 0.1 kJ mol-1 (Figure 5). As in compound 14, structurally, the chiral element is the unsymmetrical biaryl axis between the pyridone and pyridine rings. The free energy barrier to interconversion of enantiomers thus corresponds to the energy required to flip the seven-membered ring. Additional Substitution Yields Diastereomeric Atropisomers. In contrast to 5a, the 1H NMR spectra of 5b (Figure 6) is complex and consistent with a mixture of two atropisomeric diastereomers, in which a second element of axial chirality arises from the unsymmetrical ortho substitution of the phenyl ring. Many examples of diastereomeric atropisomers have been reported in which the diastereomers arise from a sp3 carbon stereocenter and an element of planar chirality.19 In contrast, diastereomers resulting from two chiral biaryl axes have been rarely reported and studied.20 (19) For a recent example see: Kitagawa, O.; Fujita, M.; Kohriyama, M.; Hasegawa, H.; Taguchi, T. Tetrahedron Lett. 2000, 41, 8539.

Tricyclic Pyridones Containing a Fused Seven-Membered Ring

FIGURE 6. 1H NMR spectra of 5b (500 MHz, d6-DMSO) at 300 and 340 K.

FIGURE 7. EXSY data for 5b at 300 and 340 K in d6-DMSO.

Acquiring the 1H NMR spectra of 5b at elevated temperature failed to simplify the spectrum (Figure 6), indicating that diastereomeric interconversion is slow on the NMR time scale. An alternative method of determining the exchange rate is via two-dimensional exchange spectroscopy (EXSY).21 The pulse sequence is identical with that used for 2D nuclear Overhauser effect spectroscopy, but attention is focused on positively signed cross-peaks which contain information about intersite exchange, rather than negative cross-peaks which denote through space NOE effects. EXSY experiments were performed in d6-DMSO at 300 and 340 K with mixing times tm of 0.1, 0.2, or 0.4 s. For an uncoupled pair of spins A and B, present in mole fractions XA and XB, with diagonal intensities IAA and IBB and cross-peak intensities IAB and IBA, respectively, the intersite exchange rate is given by

k ) (1/tm) ln[(r + 1)/(r - 1)] where

r ) 4(XAXB)(IAA + IBB)/(IAB + IBA) - (XA - XB)2 Application of these equations to the experimental data acquired for 5b (Figure 7) leads to values of k ) 0.1 s-1 at 300 K and 8 s-1 at 340 K for the interconversion of the diastereomers and hence a free energy barrier of ∆Gq ) 79.2 kJ mol-1 at 300 K. Clearly the interconversion of diastereomers is far too rapid to allow their resolution by HPLC and unsurpris(20) Zoltewicz, J. A.; Maier, N. M.; Fabian, W. M. F. J. Org. Chem. 1996, 61, 7018. (21) Perrin, C. L.; Dwyer, T. J. Chem. Rev. 1990, 90, 935.

FIGURE 8. Conformational dynamics of 5b.

ingly the chromatogram of 5b obtained using achiral reverse-phase HPLC contains a single peak. However, as for 5a, using a chiral stationary phase, two enantiomer peaks were observed for 5b. Using the same approach as for 5a, the half-lives of interconversion of the enantiomers were determined to be 22.6 and 21.8 min giving rate constants of 2.55 × 10-4 and 2.65 × 10-4 s-1. Hence, the average free energy barrier for interconverting the enantiomers of 5b is ∆Gq ) 91.8 ( 0.1 kJ mol-1 at 293 K. By NMR we can measure the rate of diastereomer interconversion; this process is too fast to be resolved by HPLC. Conversely, NMR experiments in the absence of a chiral moderator can tell us nothing about the rate of enantiomer interconversion. However, chiral HPLC allows resolution of the enantiomers of the mixture of rapidly interconverting diastereomers and has enabled the racemization rates of the interconverting diastereomers to be measured. Interconversion of diastereomers can arise from inversion of either chiral element, either rotation of the o-tolyl group, or flipping the sevenmembered ring. In contrast, the rates of racemization of 5b determined by chiral HPLC correspond to both flipping the seven-membered ring and rotation of the tolyl group. On the basis of the HPLC experiments conducted for 5a we can assume that the rate constant for the interconversion of the diastereomers of 0.1 s-1 must refer to rotation of the o-tolyl group. Hence, the rates of racemization of 22.6 and 21.8 min correspond to the flipping of the seven-membered ring. This allows the conformational dynamics of 5b to be fully described as shown in Figure 8. Conclusion Two synthetic strategies to access compounds such as 1 have now been described. The previously reported synthesis relied upon a radical-mediated cyclization to form the seven-membered ring and introduced the C5substituent as the final step.1 The new route is complementary in that the C3-substituent is introduced late in the synthesis and the seven-membered ring is closed via intramolecular alkylation of the pyridone under Mitsunobu conditions. Due to the tri-ortho-substituted biaryl bond contained in compounds such as 1, these highly substituted aromatic systems exhibit atropisomJ. Org. Chem, Vol. 67, No. 26, 2002 9357

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FIGURE 9. Summary of the conformational behavior of tricyclic pyridones.

erism and exist as isolable enantiomers. Through a combination of variable-temperature NMR, 2D EXSY experiments, and chiral HPLC a full description of the conformational behavior of these molecules has been elucidated (Figure 9).

Experimental Section General. All reagents and solvents were obtained commercially and were used as received unless otherwise indicated. Anhydrous THF, DMF, DMSO, and dichloromethane reaction solvents were also purchased commercially. All reactions were performed under a nitrogen atmosphere unless otherwise indicated. SCX resin and cartridges were purchase from Varian. 1H NMR 1D and 2D spectra were obtained at 360, 400, or 500 MHz, and chemical shifts (δ) are reported in parts per million (ppm) downfield from internal tetramethylsilane (TMS). Coupling constants (J) are reported in hertz. The first number in the parentheses which follow each peak is the number of protons represented in that peak. Mass spectra were obtained by chemical ionization in electrospray mode (ES+). Analytical HPLC was done on a Hichrom Excel KR100-3.5 C8 (150 × 4.6 mm2 i.d.) column using a variable wavelength detector with detection at 254 nm wavelength. The eluents were mixtures of acetonitrile/water and a flow rate of 1 mL/ min was used. Microanalyses were performed by Butterworth Laboratories, Teddington, Middlesex, UK. Melting points are uncorrected. 3-Bromo-4-[3-hydroxypropyl]pyridine (6). Butyllithium solution (445 mL, 2.5 M in hexane, 1.125 mol) was added over 30 min to a cooled solution of diisopropylamine (157 mL, 1.11 mol) in THF (1.5 L) keeping the temperature below 10 °C. The reaction was stirred at 5 °C for 5 min then 3-bromo-4methylpyridine (175 g, 1.02 mol) was added and the reaction heated to 50 °C for 45 min. The reaction was cooled to -20 °C and a cold (-78 °C) solution of ethylene oxide (69 g, 1.5 mol, condensed into cold THF, 500 mL) was added. The reaction temperature was maintained below 0 °C. After 30 min the reaction was quenched by the addition of water (750 mL). The layers were separated and the aqueous extracted with EtOAc. The combined organics were dried (Na2SO4) and the solvent was removed in vacuo before purification on a pad of silica (EtOAc) to afford the title compound as an oil (172 g, 78%).

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H NMR (400 MHz, CDCl3) δ 1.87-1.94 (2H, m), 2.84 (2H, dd, J ) 10, 8), 3.72 (2H, t, J ) 6), 7.19 (1H, d, J ) 5), 8.40 (1H, d, J ) 5), 8.65 (1H, s); MS (ES+) m/z 216, 218 (M + H+). 3-Bromo-4-[3-(tert-butyldimethylsilanyloxy)propyl]pyridine (7). Imidazole (19.4 g, 285.9 mmol) was added to a solution of 6 (47.5 g, 219.9 mmol) in dry dichloromethane (250 mL) followed by TBDMSCl (34.8 g, 230.9 mmol) and the reaction was stirred at room temperature for 17 h. The reaction was washed with water and dried (MgSO4), and the solvent was removed in vacuo to afford the title compound as a colorless oil (72.5 g, 100%). 1H NMR (400 MHz, CDCl3) δ 0.07 (6H, s), 0.84 (9H, s), 1.75-1.78 (2H, m), 2.71-2.75 (2H, m), 3.60 (2H, t, J ) 6), 7.10 (1H, d, J ) 5), 8.32 (1H, d, J ) 5), 8.57 (1H, s); MS (ES+) m/z 330, 332 (M + H+). 4-[3-(tert-Butyldimethylsilanyloxy)propyl]nicotinic Acid Methyl Ester (8). A solution of 7 (20.0 g, 60.6 mmol) in dry MeOH (250 mL) and DMF (250 mL) was degassed with nitrogen for 20 min. N-Ethyldiisopropylamine (31.7 mL, 181.8 mmol) and 1,3-bis(diphenylphosphino)propane (2.5 g, 6.0 mmol) were added and the solution was degassed for a further 5 min. Palladium(II) acetate (1.3 g, 6.0 mmol) was added, and carbon monoxide was bubbled through for 20 min at room temperature before heating the mixture at 95 °C for 20 h. The reaction was then allowed to cool and poured into water. The aqueous was extracted (EtOAc), and the organic layer was dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography (30% EtOAc:isohexanes) to yield the title compound as an oil (33.5 g, 88%): 1H NMR (400 MHz, CDCl3) δ 0.07 (6H,s), 0.85 (9H, s), 1.75-1.79 (2H, m), 2.96-3.00 (2H, m), 3.60 (2H, t, J ) 6), 3.86 (3H, s), 7.14 (1H, d, J ) 5), 8.52 (1H, d, J ) 5), 8.98 (1H, s); MS (ES+) m/z 310 (M + H+). 4-[3-(tert-Butyldimethylsilanyloxy)propyl]nicotinic acid (9). 8 (15.0 g, 48.5 mmol) was added to a stirred suspension of potassium trimethylsilanolate (9.4 g, 72.8 mmol) in dry Et2O (250 mL). After 48 h the solid was collected by filtration and dissolved in water (300 mL) and the pH was adjusted with citric acid (10% w/v) to pH 5. The aqueous was extracted (EtOAc × 3), the organics dried (MgSO4), and the solvent removed in vacuo to give the title compound (12.8 g 89%) as white solid, mp 84-86 °C (from EtOAc): 1H NMR (400 MHz, d6-DMSO) δ 0.07 (6H, s), 0.84 (9H, s), 1.71-1.78 (2H, m), 2.932.97 (2H, m), 3.60 (2H, t, J ) 6), 7.31 (1H, d, J ) 5), 8.55 (1H, d, J ) 5), 8.96 (1H, s), 13.25 (1H, br s); MS (ES+) m/z 296 (M + H+). 3-{4-[3-(tert-Butyldimethylsilanyloxy)propyl]pyridin3-yl}-3-oxo-2-phenylpropionic Acid Methyl Ester (10a). 1,1′-Carbonyldiimidazole (19.6 g, 120.8 mmol) was added to a solution of 9 (34 g, 115 mmol) in dry DMF (1 L). The mixture was heated at 50 °C for 90 min before cooling to -10 °C. Methyl phenylacetate (17.4 mL, 120.8 mmol) was added followed by sodium hydride (60% in mineral oil) (16.1 g, 402 mmol) in portions over 20 min. The mixture was stirred at -10 °C for 15 min and allowed to warm to room temperature for 3 h before being slowly poured into NH4Cl solution (1 L, saturated aqueous). The aqueous was extracted with EtOAc (3 × 500 mL). The combined organics were washed with water (3 × 200 mL) and brine (2 × 200 mL) and dried (MgSO4) and the solvent was removed in vacuo. The residue was purified by flash chromatography (30% EtOAc/hexanes) to afford the title compound (49.2 g, 98%) as a colorless oil. 1H NMR (400 MHz, CDCl3) mixture of ketone and enol tautomers, enol reported, δ 0.01 (6H, s), 0.85 (9H, s), 1.72-1.77 (2H, m), 2.622.66 (2H, m), 3.87 (2H, t, J ) 6), 3.72 (3H, s), 6.90-6.93 (2H, m), 7.03-7.05 (3H, m), 7.25-7.30 (1H, m), 8.10 (1H, s), 8.24 (1H, d, J ) 5), 13.2 (1H, s); MS (ES+) m/z 428 (M + H+). 3-{4-[3-(tert-Butyldimethylsilanyloxy)propyl]pyridin3-yl}-3-oxo-2-o-tolylpropionic Acid Methyl Ester (10b). N,N′-Carbonyldiimidazole (0.91 g, 5.58 mmol) was added to a solution of nicotinic acid 9 (1.5 g, 5.08 mmol) in dry DMF (50 mL). The mixture was heated at 50 °C for 90 min before cooling to -10 °C. Methyl o-tolyl acetate (0.92 g, 5.58 mmol) was added

Tricyclic Pyridones Containing a Fused Seven-Membered Ring followed by sodium hydride (60% in mineral oil) (0.71 g, 17.8 mmol) in portions over 20 min. The mixture was stirred at -10 °C for 15 min and allowed to warm to room temperature for 3 h before being slowly poured into NH4Cl solution (200 mL, saturated aqueous). The aqueous was extracted with EtOAc (3 × 100 mL). The combined organics were washed with water (3 × 50 mL) and brine (2 × 50 mL) and dried (Na2SO4) and the solvent was removed in vacuo. The residue was purified by flash chromatography (15% EtOAc/hexanes) to afford the title compound as an oil (1.69 g, 75%). 1H NMR (400 MHz, CDCl3) mixture of ketone and enol tautomers, enol reported, δ 0.00 (6H, s), 0.84 (9H, s), 1.80 (2H, pentet, J ) 6), 2.14 (3H, s), 2.60-2.70 (1H, m), 2.73-2.83 (1H, m), 3.61 (2H, t, J ) 6), 3.70 (3H, s), 6.71-6.75 (1H, m), 6.80-6.86 (1H, m), 6.95-7.03 (3H, m), 7.97 (1H, s), 8.20 (1H, d, J ) 5), 13.17 (1H, s); MS (ES+) m/z 442 (M + H+). 1-{4-[3-(tert-Butyldimethylsilanyloxy)propyl]pyridin3-yl}-2-phenylethanone (11a). Sodium chloride (7.36 g, 126 mmol) and water (3 mL, 172 mmol) were added to a solution of 10a (49.0 g, 114 mmol) in DMSO (800 mL) and the solution was heated at 150 °C. After 2 h the solution was allowed to cool and poured into water (2 L). The aqueous was extracted with 1:1 EtOAc/Et2O (5 × 800 mL). The combined organic extracts were washed with water (4 × 800 mL) and brine (2 × 800 mL) and dried (Na2SO4). The solvent was removed in vacuo and the residue was purified by flash chromatography (30% EtOAc/hexanes) to afford the title compound as an oil (29.6 g, 70%). 1H NMR (400 MHz, CDCl3) δ 0.01 (6H, s), 0.86 (9H, s), 1.60-1.69 (2H, m), 2.77-2.81 (2H, m), 3.54 (2H, t, J ) 6), 4.19 (2H, s), 7.16-7.28 (6H, m), 8.50 (1H, d, J ) 5), 8.90 (1H, s); MS (ES+) m/z 370 (M + H+). 1-{4-[3-(tert-Butyldimethylsilanyloxy)propyl]pyridin3-yl}-2-o-tolylethanone (11b). Sodium chloride (0.1 g, 1.74 mmol) and water (0.06 mL, 3.2 mmol) were added to a solution of 10b (0.7 g, 1.59 mmol) in DMSO (10 mL) and the solution was heated at 150 °C. After 30 min the solution was allowed to cool and poured into water (150 mL). The aqueous was extracted with 1:1 Et2O:EtOAc (3 × 50 mL). The organics were washed with water (2 × 50 mL) and brine (2 × 50 mL) and dried (Na2SO4). The solvent was removed in vacuo and the residue was purified by flash chromatography (20% EtOAc/ hexanes) to afford the title compound as an oil (0.465 g, 76%). 1 H NMR (400 MHz, CDCl3) δ 0.00 (6H, s), 0.86 (9H, s), 1.681.73 (2H, m), 2.23 (3H, s), 2.77-2.81 (2H, m), 3.55 (2H, t, J ) 6), 4.22 (2H, s), 7.07-7.20 (4H, m), 7.19 (1H, d, J ) 5), 8.53 (1H, d, J ) 5), 8.91 (1H, s); MS (ES+) m/z 384 (M + H+). 1-{4-[3-(tert-Butyldimethylsilanyloxy)propyl]pyridin3-yl}-3-(dimethylamino)-2-phenylpropenone (12a). 11a (29.2 g, 79 mmol) was dissolved in N,N-dimethylformamidedimethyl acetal (400 mL) and stirred for 18 h at room temperature. The N,N-dimethylformamide-dimethyl acetal was removed in vacuo and the residue azeotroped with toluene (2 × 200 mL) to afford an oil. The title compound thus produced was used without purification in subsequent reactions (33.55 g; 100%). 1H NMR (400 MHz, CDCl3) δ 0.00 (6H, s), 0.85 (9H, s), 1.77-1.81 (2H, m), 2.66 (6H, br s), 3.58 (2H, t, J ) 6), 7.07 (1H, d, J ) 5), 7.07 (1H, d, J ) 5), 7.11-7.22 (6H, m), 8.32 (1H, s), 8.34 (1H, d, J ) 5); MS (ES+) m/z 425 (M + H+). 1-{4-[3-(tert-Butyldimethylsilanyloxy)propyl]pyridin3-yl}-3-(dimethylamino)-2-o-tolylpropenone (12b). 11b (0.44 g, 1.15 mmol) was dissolved in N,N-dimethylformamidedimethyl acetal (15 mL, 105 mmol) and stirred for 8 h at 50 °C. The N,N-dimethylformamide-dimethyl acetal was removed in vacuo and the residue was azeotroped with toluene (2 × 20 mL) to afford an oil. The title compound thus produced was used without purification in subsequent reactions (0.485 g, 96%). 1H NMR (400 MHz, CDCl3) δ 0.00 (6H, s), 0.86 (9H, s), 1.79-1.85 (2H, m), 2.21 (3H, s), 2.60 (6H, br s), 2.68-2.75 (2H, m), 3.59 (2H, d, J ) 6), 6.9 (1H, br), 7.05-7.17 (5H, m), 8.35-8.41 (2H, m); MS (ES+) m/z 439 (M + H+). 4′-(3-Hydroxypropyl)-5-(4-methylthiazol-2-yl)-3-phenyl-1H-[2,3′]bipyridinyl-6-one (13a). 4-Methylthiazole-2-acet-

mide (2) (1.06 g, 6.76 mmol) was added to a solution of 12a (2.3 g, 5.41 mmol) in dry DMF (75 mL). Sodium hydride (0.87 g, 60% in mineral oil, 21.6 mmol) was added in 4 portions before the solution was stirred for 10 min at room temperature. Dry MeOH (0.22 mL, 5.4 mmol) was added and the mixture was heated at 50 °C for 2 h before being cooled to room temperature. HCl (1 N) was added until the reaction mixture was strongly acidic. After 5 min water (100 mL) was added and the pH was adjusted to 5 with NaHCO3 solution (saturated aqueous). The aqueous was extracted with EtOAc (4 × 100 mL) and the combined organics were washed with water (2 × 50 mL) and brine (2 × 50 mL) and dried (MgSO4). The solvent was removed in vacuo to 50 mL total volume during which time a white precipitate formed. The solid was collected by filtration and washed with cold EtOAc (10 mL) and Et2O (3 × 10 mL) to afford the title compound (1.502 g; 69%). Melting point 292-294 °C; 1H NMR (400 MHz, d6-DMSO) δ 1.39-1.44 (1H, m), 1.55-1.61 (1H, m), 2.27-2.34 (1H, m), 2.42-2.46 (1H, m), 2.43 (3H, s), 3.28-3.31 (2H, m), 4.47 (1H, br), 7.11 (2H, d, J ) 7), 7.20-7.27 (4H, m), 7.33 (1H, s), 8.45 (1H, s), 8.46 (1H, d, J ) 7), 8.50 (1H, s), 12.7 (1H, br s); MS (ES+) m/z 404 (M + H+). 4′-(3-Hydroxypropyl)-5-(4-methylthiazol-2-yl)-3-o-tolyl1H-[2,3′]bipyridinyl-6-one (13b). 4-Methylthiazole-2-acetmide (2) (178 mg, 1.14 mmol) was added to a solution of 12b (0. 4 g, 0.91 mmol) in dry DMF (10 mL). Sodium hydride (60% in oil) (146 mg, 3.65 mmol) was added in 4 portions. The mixture was stirred for 10 min and then heated at 50 °C for 16 h before being cooled to room temperature. The mixture was slowly poured into water (50 mL) and 1 N HCl was added until it was strongly acidic. After 10 min the pH was adjusted to 5 with NaHCO3 solution (saturated aqueous). The aqueous was extracted with EtOAc (3 × 50 mL), the combined organics were washed with water (2 × 25 mL) and brine (2 × 25 mL) dried (Na2SO4), and the solvent was removed in vacuo. The residue was purified by flash chromatography (EtOAc-5% MeOH/EtOAc) to afford the title compound as a pale solid (140 mg, 37%). Melting point 263-265 °C; 1H NMR (400 MHz, d6DMSO) δ 1.40-1.83 (2H, br m), 2.16 (3H, br s), 2.20-2.30 (2H, m), 2.41 (3H, s), 3.33-3.43 (2H, m), 4.55 (1H, t, J ) 5), 6.907.05 (1H, br m), 7.02 (1H, t, J ) 7), 7.11-7.19 (2H, m), 7.217.25 (1H, br m), 7.32 (1H, s), 8.32 (1H, s), 8.38 (1H, d, J ) 5), 8.4-8.6 (1H, br m), 12.68 (1H, s); MS (ES+) m/z 418 (M + H+). 9-(4-Methylthiazol-2-yl)-11-phenyl-6,7-dihydro-5H2,7a-diazadibenzo[a,c]cyclohepten-8-one (5a). Diethylazodicarboxylate (0.72 mL, 4.57 mmol) was added to a suspension of 13a (1.47 g, 3.65 mmol) and triphenylphosphine (1.20 g, 4.57 mmol) in dry THF (500 mL). Dissolution occurred within 5 min. After 10 min the solution was partitioned between water (300 mL) and EtOAc (300 mL). The layers were separated and the aqueous extracted with EtOAc (2 × 150 mL). The combined organics were washed with water (100 mL) and brine (100 mL) and dried (MgSO4) and the solvent was removed in vacuo. The residue was dissolved in MeOH (30 mL) and CH2Cl2 (5 mL) before loading onto SCX resin (40 g). The resin was washed with MeOH (800 mL) and then the product was eluted with 10% NH3 in MeOH (300 mL) and concentrated to 25-mL volume. The resultant crystalline solid was collected by filtration and washed with Et2O to afford the title compound as yellow needles (1.19 g, 84%). Melting point 238-240°C; HPLC (70% MeCN/H2O) Rt ) 4.8 min, 99.6%; UV-vis (MeOH) 390 nm; 1H NMR (400 MHz, CDCl3) δ 2.01-2.07 (1H, m), 2.52 (3H, s), 2.55-2.61 (1H, m), 2.75-2.83 (2H, m), 2.89 (1H, dd, J ) 13, 7), 5.32 (1H, dd, J ) 13, 5), 6.99-7.02 (2H, m), 7.05 (1H, s), 7.21-7.25 (4H, m), 8.02 (1H, s), 8.47 (1H, d, J ) 5), 8.74 (1H, s); MS (ES+) m/z 386 (M + H+); 13C NMR (100.6 MHz, CDCl3) δ 17.3, 28.6, 29.4, 42.5, 116.5, 121.6, 122.3, 123.0, 127.4, 128.6, 129.3, 129.8, 137.4, 138.0, 142.9, 147.6, 150.6, 150.7, 152.5, 159.3, 159.9. Anal. Calcd for C23H19N3OS‚0.25H2O: C, 70.83; H, 5.04; N, 10.77. Found: C, 70.89; H, 4.98; N, 10.55. 9-(4-Methylthiazol-2-yl)-11-o-tolyl-6,7-dihydro-5H-2,7adiazadibenzo[a,c]cyclohepten-8-one (5b). Diisopropyl-

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Gibson et al. azodicarboxylate (15 µL, 0.07 mmol) was added to a suspension of 13b (25 mg, 0.06 mmol) and triphenylphosphine (20 mg, 0.07 mmol) in dry THF (2 mL). Dissolution occurred within 5 min. After 10 min the reaction was loaded onto an SCX cartridge (5 g). The resin was washed with MeOH (40 mL) and then the product was eluted with 10% NH3 in MeOH (10 mL) and the solvent was removed in vacuo. The resultant solid was collected by filtration and washed with Et2O to afford the title compound as a yellow crystalline solid (19 mg, 79%). Melting point 244-245 °C; HPLC (70% MeCN/H2O) Rt ) 8.1 min, 98%; UV-vis (MeOH) 390 nm; 1H NMR (400 MHz, CDCl3) as a mixture of atropisomers, δ 1.57 (3H minor, s), 1.61 (3H major, br s), 2.01-2.07 (1H, m), 2.48 (3H minor, s), 2.572.67 (2H, m), 2.84 (1H, dd, J ) 13, 7), 3.10-3.18 (1H, m), 5.285.35 (1H, m), 6.40 (1H minor, d, J ) 7), 6.84 (1H, minor, t, J ) 7), 6.94 (1H major, d, J ) 7), 7.04 (1H minor, s), 7.05 (1H major, s), 7.13 (1H major, t, J ) 7), 7.17-7.30 (2H + 1H minor, m), 7.46 (1H major, d, J ) 7), 7.46 (1H major, d, J ) 7), 8.08 (1H major, s), 8.41 (1H minor, d, J ) 5), 8.44 (1H major, d, J ) 5), 8.60 (1H, s); MS (ES+) m/z 400 (M + H+). Determination of the Half-Life of Racemization of 5a and 5b. HPLC conditions for 5a: Equipment: HP1100 equipped with a DAD detector. Column: Chiralcel OD-H (250 × 4.6 mm i.d.). Mobile phase: 50/50 ethanol/isohexane. Flow rate: 1.5 mL/min. Detection: 380 nm. Procedure: A 1 mg/mL solution of 5a in ethanol was prepared. A 100-µL sample of this solution was injected onto the HPLC column (corresponding to 100 µg). Both peaks were collected into separate HPLC vials. Each fraction was then reinjected every 9 min and the enantiomeric excess was calculated for each reinjection; the results were analyzed over 2 half-lives. HPLC conditions for 5b: Equipment: HP1100 equipped with a DAD detector. Column: Chiralcel OD-H (250 × 4.6 mm i.d.). Mobile phase: 40/60 ethanol/isohexane. Flow rate: 1 mL/ min. Detection: 380 nm. Procedure: A 1 mg/mL solution of 5b in ethanol was prepared. A 100-µL sample of this solution was injected onto the HPLC column (corresponding to 100 µg). Both peaks were collected into separate HPLC vials. Each

9360 J. Org. Chem., Vol. 67, No. 26, 2002

fraction was then reinjected every 11 min and the enantiomeric excess was calculated for each reinjection; the results were analyzed over 2 half-lives. The half-lives of racemization (t1/2 in s) were calculated for each enantiomer in Excel 2000 and from these the rate constants (k in s-1) were derived using the equation for an irreversible first-order reaction.

k)

ln 2 2t1/2

The free energy of activation (J mol-1) was in turn calculated from the Eyring equation22

∆Gq(T) ) -RT ln

(

k kbT/h

)

where R is the universal gas constant, T is the temperature, kb is Boltzmann’s constant, and h is Planck’s constant. The free energy barrier reported is the mean of those calculated for each enantiomer ( the standard deviation. 1 H NMR Spectroscopy. 1H NMR experiments were performed on Bruker AMX-500 or DPX-400 spectrometers equipped with 5 mm BBI probeheads. Standard 2D pulse sequences supplied by Bruker as part of XWIN NMR release 2.1 were used for all experiments. Supporting Information Available: 1H NMR spectra for compounds 5a, 5b, 6, 7, 8, 9, 10a, 10b, 11a, 11b, 12a, 12b, 13a, and 13b; 13C NMR spectra for compounds 5a and 5b; chiral HPLC chromatograms of rac-5a and rac-5b and integrations and calculations for determination of racemization halflives and free energy barriers. This material is available free of charge via the Internet at http://pubs.acs.org. JO026411A (22) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds; Wiley-Interscience: New York, 1994.