Functionalized Spiro- and Fused-Ring Heterocycles via Oxidative

Jan 17, 2004 - [email protected]. Received July 22, 2003 ... In certain instances, the efficiency of oxidative demetalation was enhanced by the inc...
0 downloads 0 Views 165KB Size
Download PDF
Functionalized Spiro- and Fused-Ring Heterocycles via Oxidative Demetalation of Cyclohexadienyl Ruthenium Complexes F. Christopher Pigge,* John J. Coniglio, and Nigam P. Rath Department of Chemistry and Biochemistry, University of Missouri-St. Louis, 8001 Natural Bridge Road, St. Louis, Missouri 63121-4499 [email protected] Received July 22, 2003

Electron-rich alkoxy- and chloro-substituted azaspirocyclic cyclohexadienyl Ru(II) complexes have been converted to either azaspiro[4.5]decane derivatives or functionalized tetrahydroisoquinolines by treatment with suitable oxidizing agents. Copper(II) chloride was found to provide demetalated products in high yield relative to the other oxidants examined (FeCl3, DDQ, CAN, [Cp2Fe][PF6], phenyliodine diacetate, IBX). In certain instances, the efficiency of oxidative demetalation was enhanced by the inclusion of chloride ion additives in the reaction. Pyridinium dichromate (PDC) was also found to effect the demetalation of a wide range of cyclohexadienyl Ru complexes; however, isolated yields of metal-free products were exceedingly low. The cyclohexadienyl ruthenium complexes used in this study were prepared from (arene)Ru(II) precursors; thus, the isolation of alicyclic cyclohexadienone derivatives upon demetalation constitutes completion of a Ru-mediated dearomatization process. Introduction Synthetic manipulation of η6-arene metal complexes provides a valuable means of obtaining functionalized benzene derivatives.1 In particular, (arene)Cr(CO)3 complexes have been extensively studied, and these organometallic materials are well-recognized as versatile intermediates in the context of organic synthesis.2 Though not as thoroughly investigated, related arene-Ru(II) complexes also possess many attributes desirable in synthetic building blocks, such as ease of preparation and stability.3 Moreover, the Ru(II) center exerts a greater activating effect upon coordinated arene ligands relative to Cr(0), thus rendering arene-ruthenium derivatives ideal substrates for many reactions typical of arene metal complexes (e.g., nucleophilic aromatic addition and substitution, side-chain manipulation).1,3,4 This property has been exploited to great effect in the synthesis of a number of macrocyclic biaryl ethers and related materials from (1) (a) Semmelhack, M. F. In Comprehensive Organometallic Chemistry II; Hegedus, L. S., Ed.; Elsevier Science, Ltd.: Oxford, 1995; Vol. 12, pp 979-1038. (b) Davies, S. G.; McCarthy, T. D. In Comprehensive Organometallic Chemistry II; Hegedus, L. S., Ed.; Elsevier Science, Ltd.: Oxford, 1995; Vol. 12, pp 1039-1070. (c) Sun, S.; Dullaghan, C. A.; Sweigart, D. A. J. Chem. Soc., Dalton Trans. 1996, 4493. (d) Pearson, A. J. Iron Compounds in Organic Synthesis; Academic Press, Ltd.: London, 1994; Chapter 6. (2) (a) Uemura, M. In Advances in Metal-Organic Chemistry; Liebeskind, L. S., Ed.; JAI Press, Ltd.: Greenwich, CT, 1991; Vol. 2, pp 195-245. For selected recent examples, see: (b) Kamikawa, K.; Sakamoto, T.; Uemura, M. Synlett 2003, 516. (c) Dehmel, F.; Lex, J.; Schmalz, H.-G. Org. Lett. 2002, 4, 3915. (d) Dehmel, F.; Schmalz, H.G. Org. Lett. 2001, 3, 3579. (e) Moser, W. H.; Zhang, J.; Lecher, C. S.; Frazier, T. L.; Pink, M. Org. Lett. 2002, 4, 1981. (3) Pigge, F. C.; Coniglio, J. J. Curr. Org. Chem. 2001, 5, 757. (4) (a) Pigge, F. C.; Fang, S. Tetrahedron Lett. 2001, 42, 17. (b) Pigge, F. C.; Fang, S.; Rath, N. P. Tetrahedron Lett. 1999, 40, 2251. (c) Velarde, E. L.; Stephen, R. A.; Mansour, R. N.; Hoang, L. T.; Burkey, D. J. J. Am. Chem. Soc. 2003, 125, 1188.

CpRu(II) building blocks (Cp ) η5-cyclopentadienyl).5 Moreover, coordination of a CpRu fragment to an unsymmetrically polysubstituted arene ring introduces an element of planar chirality to the complex, and this latter feature has been recently utilized in the preparation of nonracemic biaryl derivatives.6 The ability to control the arene-activating effect of various transition metal fragments for the conversion of aromatic compounds into synthetically valuable nonaromatic alicyclic materials has emerged as an important focus of contemporary studies.7 Such dearomatization procedures are well-established for (η6-arene)Cr(CO)3 complexes as well as η2-arene osmium species.8,9 There are also noteworthy examples of metal-mediated dearomatization involving manganese, molybdenum, and rhenium complexes.10 Dearomatization reactions leading to functionalized cyclohexenes from (arene)Fe and (arene)Ru precursors, however, have not been reported.11 (5) (a) Pearson, A. J.; Zigmantas, S. Tetrahedron Lett. 2001, 42, 8765. (b) West, C. W.; Rich, D. H. Org. Lett. 1999, 1, 1819. (c) Venkatraman, S.; Njoroge, F. G.; Girijavallabhan, V.; McPhail, A. T. J. Org. Chem. 2002, 67, 3152. (d) Moriarty, R. M.; Enache, L. A.; Gilardi, R.; Gould, G. L.; Wink, D. J. Chem. Commun. 1998, 1155. (6) (a) Kamikawa, K.; Norimura, K.; Furusyo, M.; Uno, T.; Sato, Y.; Konoo, A.; Bringmann, G.; Uemura, M. Organometallics 2003, 22, 1038. (b) Kamikawa, K.; Furusyo, M.; Uno, T.; Sato, Y.; Konoo, A.; Bringmann, G.; Uemura, M. Org. Lett. 2001, 3, 3667. (7) Pape, A. R.; Kaliappan, K. P.; Ku¨ndig, E. P. Chem. Rev. 2000, 100, 2917. (8) (a) Ku¨ndig, E. P.; Cannas, R.; Laxmisha, M.; Ronggang, L.; Tchertchian, S. J. Am. Chem. Soc. 2003, 125, 5642. (b) Bernardinelli, G.; Gillet, S.; Ku¨ndig, E. P.; Liu, R.; Ripa, A.; Saudan, L. Synthesis 2001, 2040. (c) Pearson, A. J.; Gontcharov, A. V. J. Org. Chem. 1998, 63, 152. (d) Semmelhack, M. F.; Yamashita, A. J. Am. Chem. Soc. 1980, 102, 5926. (9) (a) Harman, W. D. Chem. Rev. 1997, 97, 1953. (b) Ding, F.; Kopach, M. E.; Sabat, M.; Harman, W. D. J. Am. Chem. Soc. 2002, 124, 13080 and references therein.

10.1021/jo035058l CCC: $27.50 © 2004 American Chemical Society

Published on Web 01/17/2004

J. Org. Chem. 2004, 69, 1161-1168

1161

Pigge et al. SCHEME 1

As part of continuing studies aimed at further defining the synthetic potential of (η6-arene)RuCp+ complexes, we have uncovered a general route for the preparation of novel cyclohexadienyl azaspirocyclic ruthenium complexes 2 from the corresponding N-benzyl acetoacetamide derivatives 1 (Scheme 1).12,13 The spirocyclic framework present in 2 exhibits an intriguing 2-azabicyclo[4.5]decane ring system that potentially offers numerous opportunities for stereocontrolled access to a range of derivatives, provided that suitable methods for removal of the CpRu fragment can be developed. Furthermore, cleavage of the cyclohexadienyl-Ru coordination without disruption of the spirocyclic linkage would complete a net Ru-mediated dearomatization of the benzylamine precursors. A recognized means of liberating unsaturated ligands (diene, dienyl, allyl) from transition metal centers is via the process of oxidative demetalation. For example, Fe-cyclohexadienyl complexes undergo demetalation with concomitant ligand re-aromatization upon treatment with DDQ.14 Various iron-diene complexes have been directly demetalated via oxidation with ceric ammonium nitrate (CAN), CuCl2, chromic acid (Jones reagent), and pyridinium chlorochromate (PCC).15 Likewise, (diene)CpCo(I) complexes are prone to oxidative cleavage upon treatment with FeCl3, CuCl2, and [Cp2Fe][PF6].16 Iron η3allyl-σ-alkyl complexes have been demetalated using CuCl2 and CAN.17 Pearson also has reported a CANmediated demetalation/oxygenation of Mn-dienyl derivatives.18 Finally, (η3-allyl)Mo(II) complexes undergo con(10) (a) Pearson, A. J.; Gontcharov, A. V.; Zhu, P. Y. Tetrahedron 1997, 53, 3849. (b) Roell, B. C.; McDaniel, K. F.; Vaughan, W. S.; Macy, T. S. Organometallics 1993, 12, 224. (c) Ku¨ndig, E. P.; Fabritius, C.H.; Grossheimann, G.; Robvieux, F.; Romanens, P.; Bernardinelli, G. Angew. Chem., Int. Ed. 2002, 41, 4577. (d) Meiere, S. H.; Keane, J. M.; Gunnoe, T. B.; Sabat, M.; Harman, W. D. J. Am. Chem. Soc. 2003, 125, 2024. (e) Valahovic, M. T.; Gunnoe, T. B.; Sabat, M.; Harman, W. D. J. Am. Chem. Soc. 2002, 124, 3309. (f) Chordia, M. D.; Smith, P. L.; Meiere, S. H.; Sabat, M.; Harman, W. D. J. Am. Chem. Soc. 2001, 123, 10756. (11) For an example of the conversion of a bis(arene)Ru(II) dication to cyclohexene, see: Grundy, S. L.; Smith, A. J.; Adams, H.; Maitlis, P. M. J. Chem. Soc., Dalton Trans. 1984, 1747. (12) (a) Pigge, F. C.; Coniglio, J. J.; Fang, S. Organometallics 2002, 21, 4505. (b) Pigge, F. C.; Fang, S.; Rath, N. P. Org. Lett. 1999, 1, 1851. (13) For a related (arene)Ru-mediated spirocyclization process, see: Chae, H. S.; Burkey, D. J. Organometallics 2003, 22, 1761. (14) Sutherland, R. G.; Zhang, C.; Pio´rko, A. J. Organomet. Chem. 1991, 419, 357. (15) (a) Kelly, L. F.; Dahler, P.; Narula, A. S.; Birch, A. J. Tetrahedron Lett. 1981, 22, 1433. (b) Pearson, A. J. J. Chem. Soc., Perkin Trans. 1 1980, 400. (c) Pearson, A. J.; Khetani, V. D.; Roden, B. A. J. Org. Chem. 1989, 54, 5141. (d) Limanto, J.; Tallarico, J. A.; Porter, J. R.; Khuong, K. S.; Houk, K. N.; Snapper, M. L. J. Am. Chem. Soc. 2002, 124, 14748. (16) For examples, see: (a) Tane, J. P.; Vollhardt, K. P. C. Angew. Chem., Int. Ed. Engl. 1982, 21, 617. (b) Grotjahn, D. B.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1990, 112, 5653. (c) Grotjahn, D. B.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1986, 108, 2091. (d) Etkin, N.; Dzwiniel, T. L.; Schweibert, K. E.; Stryker, J. M. J. Am. Chem. Soc. 1998, 120, 9702. (17) (a) Hirschfelder, A.; Eilbracht, P. Synthesis 1996, 488. (b) Yeh, M.-C. P.; Chuang, L.-W.; Chang, S.-C.; Lai, M.-L.; Chou, C.-C. Organometallics 1997, 16, 4435. (18) Pearson, A. J.; Khan, M. N. I.; Clardy, J. C.; Cun-heng, H. J. Am. Chem. Soc. 1985, 107, 2748.

1162 J. Org. Chem., Vol. 69, No. 4, 2004

SCHEME 2

trolled oxidation in the presence of CuCl2, CAN, and pyridinium dichromate (PDC) to give metal-free enones.19 We report herein detailed results of our studies directed toward the development of an oxidation-based means for the demetalation of cyclohexadienyl complexes of the type 2. A variety of oxidants and cyclohexadienyl substrates were examined, and the combination of CuCl2 and electron-rich Ru complexes was found to afford either spiro- or fused-ring heterocyclic metal-free products in high yield. Interestingly, the efficiency of certain other nonhalogenated oxidants was found to depend on the presence of added chloride ion. A preliminary account of this work has recently appeared.20 Results and Discussion Initially, several oxidants were screened for their ability to facilitate demetalation of test substrate 3. Complex 3 was used in these experiments as it was envisioned that the presence of a methoxy substituent would aid oxidation and production of “quinone-like” diene 4. Of the oxidation conditions examined (vide infra), CuCl2 in ethanol was found to be superior, and crossconjugated dienone 4 was indeed obtained in virtually quantitative yield (Scheme 2). At least 2 equiv of CuCl2 was necessary for complete consumption of the starting complex, and reactions employing less than this amount gave a mixture of 4 and unreacted 3 in nearly equal quantities. This requirement is consistent with a demetalation process that entails two single-electrontransfer steps. Reactions performed in THF also gave dienone 4 in high yield; however, MeCN and CH2Cl2 were unsatisfactory solvents. The structure of 4 was assigned on the basis of 1D and 2D NMR spectroscopic measurements and confirmed through single-crystal X-ray diffractometry.20 Particularly diagnostic signals present in the 1H NMR spectrum of 4 include a pair of doublets arising from the enone group (δ 6.25 and 6.78 ppm, J ) 9.9 Hz), and the spirocyclic quaternary carbon at 44.2 ppm in the 13C NMR spectrum. Spirocycle 4 can be delivered in synthetically useful quantities as demetalation on a gram scale proceeded in 82% isolated yield. Dimethoxy complex 5 also underwent demetalation to produce vinylogous ester 6 exclusively. In a similar fashion, cyclohexadienyl complexes with terminally positioned methoxy substituents afforded conjugated spirocyclic dienones upon treatment with CuCl2 (Scheme 3). In contrast to the reactions shown in (19) (a) Yin, J.; Liebeskind, L. S. J. Am. Chem. Soc. 1999, 121, 5811. (b) Malinakova, H. C.; Liebeskind, L. S. Org. Lett. 2000, 2, 4083. (c) Moretto, A. F.; Liebeskind, L. S. J. Org. Chem. 2000, 65, 7445. (d) Arraya´s, R. G.; Liebeskind, L. S. J. Am. Chem. Soc. 2001, 123, 6185. (e) Alcudia, A.; Arraya´s, R. G.; Liebeskind, L. S. J. Org. Chem. 2002, 67, 5773. (20) Pigge, F. C.; Coniglio, J. J.; Rath, N. P. Org. Lett. 2003, 5, 2011.

Functionalized Spiro- and Fused-Ring Heterocycles SCHEME 3

Scheme 2, however, dienes 8 and 10 were obtained in yields of only 30-40% after purification by silica gel chromatography. Analysis (1H NMR) of the crude reaction mixture obtained after exposure of 7 to CuCl2 revealed the presence of dienone 8 as well as a second compound tentatively formulated as Ru-diene complex 11. This assignment was based on the appearance of a singlet at δ ) 5.18 ppm and multiplets at δ ) 5.93, 5.31, and 4.69 ppm (relative integration of 5:1:1:2) corresponding to the Cp and coordinated olefinic hydrogens, respectively. In an effort to improve the isolated yield of metalfree product 8, copper salts were filtered from the reaction and the filtrate was stirred under an atmosphere of CO for several hours. Purification by chromatography now gave 8 in 50% yield as well as CpRu(CO)2Cl21 in 46% yield, presumably derived from ligand substitution of 11.22,23 The use of P(OEt)3 in place of CO further improved the yield of both 8 and 10 (Scheme 3) while also leading to isolation of small amounts of CpClRu[P(OEt)3]2.24 In connection with efforts aimed at improving the demetalation of 7, an unusual ring-opened byproduct was also isolated and characterized. As shown in eq 1,

treatment of 7 with CuCl2 in THF followed by addition of aqueous NH4Cl solution resulted in generation of the expected dienone 8 (albeit in low yield) and anisole derivative 12 in 11% yield. Structural assignment of 12 from spectroscopic data was complicated by the presence of tautomers and rotamers; thus, the structure was established on the basis of single-crystal X-ray diffractometry (enol tautomer, see Supporting Information). It is speculated that 12 is formed via hydrolysis of an N-acyl (21) Haines, R. J.; DuPreez, A. L. J. Chem. Soc., Dalton Trans. 1972, 944. (22) Filtration of the Cu salts prior to exposure to CO (and P(OEt)3) was necessary in order to achieve demetalation in high yield. Treatment of 7 with CuCl2 under a CO atmosphere was not successful. (23) For examples of similar ligand substitution reactions involving discrete Ru-diene complexes, see: Bosch, H. W.; Hund, H.-U.; Nietlispach, D.; Salzer, A. Organometallics 1992, 11, 2087. (24) Merlic, C. A.; Pauly, M. E. J. Am. Chem. Soc. 1996, 118, 11319.

SCHEME 4

iminium ion, in turn generated from spirolactam ring opening of 7 during Cu-mediated oxidation (vide infra). No attempt was made to optimize the production of 12, and this material was not detected under alternative demetalation conditions. The course of CuCl2-induced oxidative demetalation is significantly altered if an electron-donating methoxy substituent is present at the 2-position of the cyclohexadienyl ligand (Scheme 4). In these instances a facile skeletal rearrangement occurs that involves spirocycle cleavage and vinyl group migration to afford tetrahydroisoquinolinone products in good yield. This reaction manifold appears to compete favorably with formation of conjugated dienone products as indicated by the ratio of 16a:16b obtained from demetalation of 15.25 Furthermore, the rearrangement pathway seems to occur in preference to formation of cross-conjugated dienones as 18 was formed exclusively from 17. Additionally, the piperonyl-derived complex 21 affords 22 upon treatment with CuCl2 (eq 2). The rearrangement pathway operative

in the preceding reactions can be rationalized by invoking the formal intermediacy of a cyclohexadienyl cation-like species, and as such the process resembles a dienolphenol rearrangement.26 A similar oxidative demetalation/rearrangement process has been observed in certain CpCo(I) diene complexes studied by Grotjahn and Vollhardt.16b Despite the loss of the stereochemically rich spirocyclic ring system, this ruthenium-based protocol nonetheless provides a relatively concise means of accessing functionalized tetrahydroisoquinoline derivatives well-suited for subsequent synthetic manipulation. (25) The structure of tetrahydroisoquinoline 16a has been determined using X-ray crystallographic analysis; see Supporting Information. (26) Vitullo, V. P.; Grossman, N. J. Am. Chem. Soc. 1972, 94, 3844.

J. Org. Chem, Vol. 69, No. 4, 2004 1163

Pigge et al. TABLE 1. Alternative Oxidative Demetalation Conditions for Conversion of Cyclohexadienyl Complex 3 to Dienone 4a entry

oxidant

solvent

additive

time

% yield 4

1 2 3 4 5 6 7 8 9 10 11 12

FeCl3 CAN CAN DDQ DDQ [Cp2Fe]+ [Cp2Fe]+ PIDAc PIDA PIDA IBXd IBX

EtOH acetone acetone CH2Cl2 CH2Cl2 EtOH EtOH CH2Cl2 CH2Cl2 CH2Cl2 DMSOe DMSOe

none none aq NaCl none aq NaCl none aq NaCl none aq NaCl solid NaCl none aq NaCl

15 min 10 min 10 min 2h 45 min 16 h 45 min 45 min 45 min 45 min 24 h 16 h

94 7 7 + 53b 17 36 24 60 30 41 38 54 + 31f 46

a All reactions performed with 3 equiv of oxidant at room temperature unless otherwise indicated. b 53% hydrolyzed product 23. c Phenyliodine diacetate. d o-Iodoxylbenzoic acid. e Reaction performed at 90 °C. f Unreacted starting material.

In developing the Cu(II)-based demetalation process described above, a number of alternative oxidizing agents were also examined. Once again, methoxy-substituted complex 3 was employed as the test substrate; the results of these studies are summarized in Table 1. Only FeCl3 rivaled CuCl2 in terms of reaction efficiency and yield. Organic oxidants CAN and DDQ proved to be completely unsatisfactory (entries 2 and 4), as was ferricinium ion (entry 6). Hypervalent iodine oxidants were also investigated as shown in entries 8 and 11. Phenyliodine diacetate (PIDA, iodine(III)) afforded 4 in 30% yield, while IBX (iodoxylbenzoic acid, iodine(V))27 gave 4 in improved 54% yield (78% based on recovered starting material). Periodinane reagents are being increasingly employed as mild oxidizing agents in organic chemistry,28 but their use in organometallic chemistry appears largely unexplored. Though not the reagents of choice in the current application, availability, mild reaction conditions, and experimental simplicity render these materials attractive alternatives to more traditional oxidizing agents. The presumed intermediacy of chlororuthenium(II) complex 11 in the reaction of 7 and CuCl2 as discussed previously may indicate that the presence of a potentially ligating anion (i.e., chloride) is important in the demetalation process. This feature may partially account for the success of CuCl2 and FeCl3 in effecting demetalation relative to the other non-halogen-containing oxidants examined. Consequently, reactions involving this latter class of oxidant were reinvestigated in the presence of an excess of chloride ion additive. As revealed in Table 1 (entry 3), treatment of 3 with CAN in the presence of saturated aqueous NaCl solution afforded 4 as a minor product along with 23 in 53% yield. As 23 is obtained from hydrolysis of the enol ether functionality in 4, the overall yield for demetalation is significantly improved. Similarly, the addition of NaCl to DDQ and [Cp2Fe][PF6] oxidation reactions resulted in shorter reaction times and an approximate doubling of the isolated yield of 4 (Table 1, entries 5 and 7). The effect of added chloride ion on (27) Frigerio, M.; Santagostino, M.; Sputore, S. J. Org. Chem. 1999, 64, 4537. (28) (a) Nicolaou, K. C.; Montagnon, T.; Baran, P. S.; Zhong, Y.-L. J. Am. Chem. Soc. 2002, 124, 2245 and references therein. (b) Wirth, T. Angew. Chem., Int. Ed. 2001, 40, 2812. (c) Moriarty, R. M.; Prakash, O. Org. React. 2001, 57, 327.

1164 J. Org. Chem., Vol. 69, No. 4, 2004

reactions involving hypervalent iodine reagents, however, was less dramatic. The use of either aqueous NaCl or solid NaCl (50 equiv) in combination with PIDA had no significant effect on the reaction outcome. Aqueous NaCl in combination with IBX did lead to complete consumption of the starting complex 3 after 16 h, but the yield of 4 was only 46%. Although the fate of the CpRu(II) fragment after oxidative demetalation is largely unknown, the isolation of CpClRu[P(OEt)3]2 from CuCl2mediated demetalation of 7 and the positive effect of added chloride ion in many of the reactions shown in Table 1 appears significant, and in most cases the presence of a viable anionic ligand is important for controlled demetalation of cyclohexadienyl complex 3. It will be interesting to see if other demetalation procedures also can benefit from judicious choice of reaction additive.29 Electron-rich alkoxy-substituted cyclohexadienyl ruthenium complexes afford either spirocyclic dienone or tetrahydroisoquinoline products upon oxidative demetalation. In addition, chloro-substituted complexes also yield rearranged tetrahydroisoquinoline derivatives after treatment with CuCl2 (Scheme 5). Both alkoxy (methoxy) and chloro substituents are nominally electron-releasing groups, and this property appears crucial for successful demetalation. Indeed, a general means of demetalating other cyclohexadienyl complexes devoid of an electronreleasing substituent has not yet been uncovered. For example, treatment of unsubstituted complex 30 with CuCl2 gave numerous unidentified products in low yield. SCHEME 5

Liebeskind encountered similar difficulties in effecting demetalation of various (η3-allyl)Mo(II) complexes.19 A general solution to this problem was recently disclosed with the development of a pyridinium dichromate (PDC)based oxidative demetalation protocol.19d,e Significantly, this procedure successfully induced decomplexation of the metal center from unsubstituted cyclic η3-allyl ligands with concomitant oxygenation at the allylic terminus. In the hope that this method also would be applicable for demetalation of Ru-cyclohexadienyl complexes, 30 was (29) For a review of halide effects in organometallic chemistry, see: Fagnou, K.; Lautens, M. Angew. Chem., Int. Ed. 2002, 41, 26.

Functionalized Spiro- and Fused-Ring Heterocycles

exposed to conditions described by Liebeskind (3 equiv of PDC, SiO2, CH2Cl2, rt).19e Encouragingly, this treatment did result in production of metal-free dienones 4 and 8 (1:2 ratio, respectively), albeit in somewhat modest 48% overall yield (eq 3). Presumably, oxygenation of the

ligand occurs via addition of H2O to either the 1- or 3-position of the cyclohexadienyl ligand during removal of the metal center. Subsequent oxidation of alcohol intermediates by excess PDC gives the isolated products. The ratio of 4:8 indicates that there is no preference for addition of H2O to a terminal vs internal dienyl carbon. The viability of PDC as a demetalating agent for other spirocyclic complexes was also examined. Unfortunately, the procedure did not emerge as a general means of decomplexation and metal-free dienones were isolated in low yield, if at all. Selected results of this study are illustrated in Table 2. Exposure of methyl-substituted substrate 31 (a complex that is not demetalated successfully with CuCl2) to Liebeskind’s PDC demetalation conditions did, in fact, result in generation of dienone 32, but in only 14% isolated yield (entry 1). Isomeric methylsubstituted complexes, however, either did not react or did not react cleanly (entries 2 and 3). Even electronrich substrates reacted only sluggishly to provide dienones 8 and 4 in modest yield (especially when compared to reactions involving CuCl2). Interestingly, treatment of 24 with PDC also resulted in formation of 8, necessitating formal oxygen for chlorine substitution in the course of demetalation (entry 6). Attempts to improve the isolated yields of the demetalated products through the use of chloride ion additives were unsuccessful. Although a truly general method for demetalation of azaspirocyclohexadienyl ruthenium complexes has not yet been developed, a high-yielding procedure suitable for conversion of electron-rich complexes to metal-free cyclohexadienone and/or tetrahydroisoquinoline derivatives has been realized. A plausible mechanistic rationale to account for the formation of spirodienone products is presented in Scheme 6. Initial one-electron oxidation of a substrate such as 7 affords the corresponding radical cation 34. Formal oxidation of the cyclohexadienyl ligand and concomitant reduction of the Ru center results in Ru(I) intermediate 35. A second one-electron oxidation in the presence of chloride ion then gives η4-Ru(II) complex 11. Dissociation of the CpRuCl fragment (facilitated by the presence of CO or P(OEt)3) then provides the observed dienone products. In reactions involving substrates such as 3, a similar sequence of events results in generation of cross-conjugated complexes analogous to 11. The lack of a 1,3-diene functional group renders the organic species a poor ligand for Ru; hence dissociation occurs readily in the absence of added ligands. The isolation of anisole derivative 12 can be accommodated by invoking nitrogen-assisted ring-opening of radical cation 34. The resulting partially coordinated arene complex 36 then

TABLE 2. PDC-Mediated Demetalation of Azaspirocyclic Cyclohexadienyl Ruthenium Complexesa

a Conditions: substrate, PDC (3 equiv), SiO , CH Cl , 24-36 2 2 2 h. b Recovered starting material. c Other unidentified products also present.

undergoes further oxidation, decomplexation, and hydrolysis to give 12. In a similar fashion, tetrahydroisoquinoline products may result from rearrangement of radical cation 38, in turn derived from a cyclohexadienyl complex such as 13 (Scheme 7). Rearomatization via elimination and ruthenium oxidation then affords 14. The fate of the ruthenium fragment is currently unknown. As discussed previously, the rearrangement pathway appears to take precedence over formation of cross-conjugated spirodienone products (e.g., conversion of 17 to 18 and 21 to 22) and to be competitive with formation of conjugated dienones (e.g., conversion of 15 to 16a,b). In summary, the oxidative demetalation of functionalized spirocyclic cyclohexadienyl Ru(II) complexes has been investigated. Electron-rich methoxy-substituted and chloro-substituted complexes proved to be ideal substrates with CuCl2 serving as the oxidant. The products of demetalation, either azaspiro[4.5]decane derivatives or tetrahydroisoquinolines, were formed as a function of cyclohexadienyl substitution pattern. The reactivity of other oxidants was also examined and in certain cases the efficiency of demetalation was found to depend on the presence of added chloride ion. The spirodienone and tetrahydroisoquinoline derivatives obtained in the course of this study are well-suited for further synthetic elaboration, and work aimed at demonstrating the utility of these heterocyclic building blocks is underway. Finally, it is noteworthy that formation of the alicyclic dienones shown in Schemes 2 and 3 formally completes a Rumediated dearomatization of benzylamine precursors. Studies designed to expand the scope of this intriguing process are also in progress. J. Org. Chem, Vol. 69, No. 4, 2004 1165

Pigge et al. SCHEME 6

SCHEME 7

Experimental Section General Procedure for Oxidative Demetalation of Cyclohexadienyl-Ru Complexes using CuCl2. The demetalation of 3 is representative. Substrate 3 (53 mg, 0.13 mmol) and CuCl2 (34 mg, 0.26 mmol) were combined in 5 mL of EtOH, and the resulting mixture was stirred at room temperature for 15 min. During this time a red solid precipitated from the reaction mixture. This solid was removed by filtration, and the filtrate was partitioned between CH2Cl2 and brine. The layers were separated, and the aqueous phase was re-extracted with CH2Cl2 (×2). The combined organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by radial chromatography (SiO2, EtOAc) to afford 4 (30 mg, 99%) as a yellow solid: mp 164 °C; Rf ) 0.40 (EtOAc). 1H NMR (300 MHz, CDCl3) δ 2.46 (s, 3H), 2.90 (s, 3H), 3.28 (s, 2H), 3.53 (s, 3H), 6.25 (d, J ) 9.9 Hz, 2H), 6.78 (d, J ) 9.9 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ 12.9, 30.1, 44.2, 54.4, 106.1, 127.8, 150.9, 164.4, 168.6, 186.3. IR (thin film) ν (cm-1) 3030, 2952, 2913, 1660.8, 1622, 1402, 1262, 1061. HRMS (EI) calcd for C13H15NO3 233.1052 [M]+, found 233.1053. Anal. Calcd for C13H15NO3: C, 66.94; H, 6.48; N, 6.00. Found: C, 66.85; H, 6.39; N, 6.11. Performing the reaction described above on 1.00 g of 3 provided 0.46 g of 4 (82%). Azaspiro[4.5]decane Derivative 6. Using the general procedure described above, 5 (51 mg, 0.12 mmol) yielded 6 (22

1166 J. Org. Chem., Vol. 69, No. 4, 2004

mg, 73%) as a colorless solid: mp 149 °C; Rf ) 0.58 (EtOAc/ MeOH 5:1). 1H NMR (300 MHz, CDCl3) δ 2.46 (s, 3H,), 2.92 (s, 3H,), 3.18 (d, J ) 9.8 Hz, 1H,), 3.48 (d, J ) 9.8 Hz, 1H,), 3.52 (s, 3H,), 3.57 (s, 3H), 5.63 (d, J ) 1.4 Hz, 1H), 6.16 (dd, J ) 9.7, 1.4 Hz, 1H), 6.54 (d, J ) 9.7 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 12.5, 30.0, 46.0, 54.3, 54.8, 56.0, 102.6, 107.9, 126.3, 146.4, 163.2, 168.4, 176.2, 188.6. IR (KBr) ν (cm-1) 1673, 1654. HRMS (EI) calcd for C14H17NO4 263.1158 [M]+, found 263.1157. Anal. Calcd for C14H17NO4: C, 63.87; H, 6.51; N, 5.32. Found: C, 63.66; H, 6.46; N, 5.28. Azaspiro[4.5]decane Derivative 8. Conjugated dienone 8 was prepared from 7 (53 mg, 0.13 mmol) using the general procedure. The crude product mixture was dissolved in THF (∼5 mL), and P(OEt)3 (2.2 equiv based on starting Ru complex) was added. The resulting solution was stirred at room temperature for ∼3 h. After evaporation of the solvent, the residue was purified by radial chromatography (SiO2, EtOAc) to afford 8 (21 mg, 70%) as a yellow crystalline solid: mp 120-123 °C; Rf ) 0.50 (EtOAc). 1H NMR (300 MHz, CDCl3) δ 2.39 (s, 3H), 2.89 (s, 3H), 3.09 (d, J ) 9.4 Hz, 1H), 3.44 (d, J ) 9.4 Hz, 1H), 3.47 (s, 3H), 6.14 (d, J ) 9.8 Hz, 1H), 6.18-6.27 (m, 2H), 7.01 (ddd, J ) 9.8, 5.1, 2.6 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 12.2, 30.1, 53.0, 54.0, 56.9, 112.9, 119.3, 126.7, 140.7, 142.3, 161.2, 167.7, 202.6. IR (thin film) ν (cm-1) 1663, 1629. HRMS (EI) calcd for C13H15NO3 233.1052 [M]+, found 233.1051. Anal. Calcd for C13H15NO3: C, 66.94; H, 6.48; N, 6.00. Found: C, 66.83; H, 6.49; N, 5.95. Azaspiro[4.5]decane Derivative 10. Using the procedure described for the preparation of 8, complex 9 (56 mg, 0.13 mmol) provided 10 (30 mg, 92%) as a yellow solid: mp 131134 °C; Rf ) 0.43 (EtOAc). 1H NMR (300 MHz, acetone-d6) δ 2.36 (s, 3H), 2.83 (s, 3H), 3.18 (d, J ) 9.2 Hz, 1H), 3.36 (d, J ) 9.2 Hz, 1H), 3.49 (s, 3H), 3.61 (s, 3H), 5.30 (d, J ) 3.1 Hz, 1H), 6.03 (dd, J ) 10.2, 0.5 Hz, 1H), 6.90 (dd, J ) 10.2, 3.1 Hz, 1H). 13C NMR (75 MHz, acetone-d6) δ 11.9, 29.8, 51.8, 54.3, 55.4, 59.1, 109.6, 116.0, 127.8, 141.2, 150.7, 160.8, 167.8, 201.9. IR (thin film) ν (cm-1) 1672, 1639. HRMS (EI) calcd for C14H17NO4 263.1158 [M]+, found 263.1157. Anal. Calcd for C14H17NO4: C, 63.87; H, 6.51; N, 5.32. Found: C, 63.66; H, 6.63; N, 5.30. 2-(2′-Methoxyphenyl)-N-methyl Acetoacetamide (12). Complex 7 (200 mg, 0.48 mmol) dissolved in THF (5 mL) was treated with CuCl2 (130 mg, 0.97 mmol) at room temperature. After 45 min, 0.24 mL (0.58 mmol) of 2.4 M aqueous NH4Cl solution was added, and the reaction was maintained for 16 h. Insoluble material was filtered from the reaction mixture, and the residue was partitioned between H2O and CH2Cl2. The layers were separated, and the aqueous phase was re-extracted with additional CH2Cl2. The combined organic layer was

Functionalized Spiro- and Fused-Ring Heterocycles washed with brine and dried over anhydrous MgSO4. Filtration, removal of the solvent, and purification of the residue by radial chromatography (SiO2, EtOAc) afforded 12 (12 mg, 11%) along with 8 (30 mg, 27%): colorless solid; mp 83-85 °C; Rf ) 0.73 (EtOAc). 1H NMR (300 MHz, CDCl3, mixture of rotamers/ tautomers) δ 1.57 (s, 0.3H), 1.71 (s, 2.7H), 2.76 (d, J ) 4.9 Hz, 2.7H), 2.83 (d, J ) 4.9 Hz, 0.3H), 3.80 (s, 2.7H), 3.86 (s, 0.3H), 5.02 (br s, 1H), 6.92-7.02 (m, 2H), 7.13 (dd, J ) 7.4, 1.5 Hz, 1H), 7.36 (ddd, J ) 8.7, 7.0, 1.5 Hz, 1H), 14.75 (s, 1H). 13C NMR (75 MHz, CDCl3, mixture of rotamers/tautomers) δ 19.7, 26.3, 29.9, 55.8, 60.1, 100.2, 111.6, 121.3, 124.0, 130.0, 133.6, 158.3, 171.0, 172.9. IR (KBr) ν (cm-1) 3366, 1629. HRMS (EI) calcd for C12H15NO3 221.1052 [M]+, found 221.1050. Tetrahydroisoquinoline Derivative 14. Application of the general demetalation procedure as described for the preparation of 4 to complex 13 (51 mg, 0.12 mmol) gave 7-methoxy tetrahydroisoquinoline 14 (17 mg, 55%) as a dark yellow solid: mp 152 °C; Rf ) 0.58 (EtOAc). 1H NMR (300 MHz, CDCl3) δ 2.53 (s, 3H), 3.09 (s, 3H), 3.77 (s, 3H), 3.81 (s, 3H), 4.28 (s, 2H), 6.67 (d, J ) 2.6 Hz, 1H), 6.82 (dd, J ) 8.7, 2.6 Hz, 1H), 7.67 (d, J ) 8.7 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 15.1, 35.0, 52.8, 54.9, 55.5, 109.6, 110.2, 112.6, 125.7, 129.8, 133.4, 157.6, 160.5, 168.3. IR (thin film) ν (cm-1) 1674. HRMS (EI) calcd for C14H17NO3 247.1208 [M]+, found 247.1210. Anal. Calcd for C14H17NO3: C, 68.00; H, 6.93; N, 5.66. Found: C, 67.84; H, 6.99; N, 5.66. Tetrahydroisoquinoline Derivative 16a and Azaspiro[4.5]decane Derivative 16b. Using the general demetalation procedure, complex 15 (52 mg, 0.12 mmol) yielded 16a (18 mg, 56%) and 16b (10 mg, 32%) after purification by radial chromatography. Compound 16a: yellow solid, mp 125-126 °C; Rf ) 0.58 (EtOAc). 1H NMR (300 MHz, CDCl3) δ 2.53 (s, 3H), 3.10 (s, 3H), 3.77 (s, 3H), 3.83 (s, 3H), 3.88 (s, 3H), 4.39 (s, 2H), 6.85 (d, J ) 8.7 Hz, 1H), 7.44 (d, J ) 8.7 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 15.1, 35.1, 46.8, 54.9, 56.1, 61.0, 109.4, 111.2, 124.3, 126.3, 126.5, 143.8, 150.1, 160.7, 168.2. IR (thin film) ν (cm-1) 1677. HRMS (EI) calcd for C15H19NO4 277.1314 [M]+, found 277.1313. Anal. Calcd for C15H19NO4: C, 64.97; H, 6.91; N, 5.05. Found: C, 64.59; H, 6.76; N, 4.98. Compound 16b: yellow oil, Rf ) 0.40 (EtOAc). 1H NMR (300 MHz, CDCl3) δ 2.38 (s, 3H), 2.91 (s, 3H), 3.11 (d, J ) 9.2 Hz, 1H), 3.48 (s, 3H), 3.54 (d, J ) 9.2 Hz, 1H), 3.74 (s, 3H), 5.90 (dd, J ) 9.0, 1.7 Hz, 1H), 6.08-6.17 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 12.2, 30.2, 54.3, 54.5, 55.6, 57.2, 110.7, 113.6, 118.4, 133.5, 152.1, 160.6, 167.7, 197.4. IR (thin film) ν (cm-1) 1673. HRMS (EI) calcd for C14H17NO4 263.1158 [M]+, found 263.1159. Tetrahydroisoquinoline Derivative 18. Using the general demetalation procedure, 18 (31 mg, 90%) was obtained from 55 mg (0.12 mmol) of 17: yellow oil, Rf ) 0.45 (EtOAc). 1H NMR (500 MHz, CDCl ) δ 2.52 (s, 3H), 3.08 (s, 3H), 3.77 3 (s, 3H), 3.86 (s, 6H), 4.26 (s, 2H), 6.62 (s, 1H), 7.33 (s, 1H). 13C NMR (125 MHz, CDCl3) δ 15.1, 34.9, 52.4, 54.9, 56.2, 56.2, 108.1, 109.8, 112.2, 124.5, 125.7, 147.2, 147.6, 160.5, 168.1. IR (thin film) ν (cm-1) 1637. HRMS (EI) calcd for C15H19NO4 277.1314 [M]+, found 277.1316. Tetrahydroisoquinoline Derivative 20. Using the general demetalation procedure, 19 (82 mg, 0.18 mmol) yielded 20 (39 mg, 82%) as a yellow oil: Rf ) 0.61 (EtOAc). 1H NMR (500 MHz, acetone-d6) δ 2.30 (s, 3H), 2.81 (s, 1H), 3.02 (s, 3H), 3.80 (s, 3H), 3.84 (s, 3H), 4.33 (d, J ) 16.0 Hz, 1H), 4.64 (d, J ) 16.0 Hz, 1H), 6.45 (d, J ) 2.2 Hz, 1H), 6.49 (d, J ) 2.2 Hz, 1H). 13C NMR (125 MHz, acetone-d6) δ 30.4, 34.4, 53.3, 55.8, 56.1 (two coincident carbon signals, based on DEPT90 and HMQC spectroscopic data), 98.0, 102.5, 113.8, 134.8, 157.9, 161.4, 165.8, 203.6. IR (thin film) ν (cm-1) 1719, 1647. HRMS (EI) calcd for C14H17NO4 263.1158 [M]+, found 263.1158. Tetrahydroisoquinoline Derivative 22. Compound 22 was prepared from 21 (53 mg, 0.12 mmol) using the general demetalation procedure. Yield: 23 mg (73%); yellow oil, Rf ) 0.36 (EtOAc/hexanes 1:1). 1H NMR (300 MHz, CDCl3) δ 2.50 (s, 3H), 3.07 (s, 3H), 3.76 (s, 3H), 4.19 (s, 2H), 5.94 (s, 2H),

6.59 (s, 1H), 7.22 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 15.1, 34.9, 52.5, 54.9, 101.1, 105.3, 109.0, 109.9, 125.7, 126.9, 145.6, 146.5, 160.6, 168.1. IR (neat) ν (cm-1) 1636. HRMS (EI) calcd for C14H15NO4 261.1001 [M]+, found 261.0998. Azaspiro[4.5]decane Derivative 23. To a solution of 3 (50 mg, 0.12 mmol) in 6 mL of acetone was added ∼6 drops of brine and 200 mg (0.37 mmol) of CAN. The resulting dark brown reaction mixture was stirred at room temperature for 10 min. The solvent was then evaporated, and the residue was partitioned between CH2Cl2 and brine. The layers were separated, and the organic phase was dried over anhydrous MgSO4. Filtration and removal of the solvent afforded a dark residue that was subsequently purified by radial chromatography (1:1 hexanes/EtOAc) to yield 4 (1.8 mg, 7%) and 23 (14 mg, 53%): colorless solid; mp 154-157 °C; Rf (EtOAc) ) 0.48. 1 H NMR (300 MHz, CDCl3, mixture of tautomers) δ 1.68 (s, 2.4H), 2.28 (s, 0.6H), 2.91 (s, 2.4H), 2.95 (s, 0.6H), 3.30 (d, J ) 10.0 Hz, 0.2H), 3.41 (s, 1.6H), 3.62 (s, 0.2H), 3.63 (d, J ) 10.0 Hz, 0.2H), 6.31 (m, 1.8H), 6.37 (m, 0.2H), 6.83-6.89 (m, 1.8H), 7.08 (dd, J ) 10.4, 3.0 Hz, 0.2H), 12.37 (s, 0.8H). 13C NMR (75 MHz, CDCl3, mixture of tautomers) δ 17.5, 29.5, 30.3, 32.5, 42.8, 44.3, 55.7, 56.2, 63.0, 99.9, 128.3, 129.9, 131.2, 146.6, 148.8, 150.3, 167.1, 168.5, 172.1, 184.8, 185.1, 202.5. IR (neat) ν (cm-1) 3272, 1660, 1623. HRMS (EI) calcd for C12H13NO3 219.0895 [M]+, found 219.0895. Tetrahydroisoquinoline Derivative 25. Using the general CuCl2 demetalation procedure, 25 (7.0 mg, 22%) was obtained from 52 mg (0.12 mmol) of 24: yellow oil, Rf ) 0.64 (EtOAc). 1H NMR (500 MHz, acetone-d6) δ 2.52 (s, 3H), 3.06 (s, 3H), 3.80 (s, 3H), 4.43 (s, 2H), 7.19-7.25 (m, 2H), 7.67 (dd, J ) 7.5, 1.3 Hz, 1H). 13C NMR (125 MHz, acetone-d6) δ 15.1, 34.7, 49.8, 55.3, 109.3, 126.5, 128.2, 128.6, 130.5, 130.8, 136.6, 163.8, 167.5. IR (thin film) ν (cm-1) 1645. HRMS (EI) calcd for C13H14ClNO2 251.0713 [M]+, found 251.0714. Tetrahydroisoquinoline Derivative 27. Compound 27 (18 mg, 60%) was obtained from 26 (50 mg, 0.12 mmol) using the general demetalation procedure: yellow oil, Rf ) 0.43 (EtOAc). 1H NMR (500 MHz, acetone-d6) δ 2.50 (s, 3H), 3.01 (s, 3H), 3.81 (s, 3H), 4.33 (s, 2H), 7.19-7.31 (m, 2H), 7.71 (d, J ) 8.3 Hz, 1H). 13C NMR (125 MHz, acetone-d6) δ 15.0, 34.5, 52.1, 55.2, 109.4, 125.5, 127.2, 130.8, 130.9, 133.2, 135.5, 163.4, 167.7. IR (thin film) ν (cm-1) 1643. HRMS (EI) calcd for C13H14ClNO2 251.0713 [M]+, found 251.0713. Tetrahydroisoquinoline Derivative 29. Using the general demetalation procedure, 28 (52 mg, 0.12 mmol) afforded 26 mg (84%) of 29 as a yellow solid: mp 96-98 °C; Rf ) 0.72 (EtOAc). 1H NMR (500 MHz, acetone-d6) δ 2.52 (s, 3H), 3.01 (s, 3H), 3.84 (s, 3H), 4.32 (s, 2H), 7.13 (dd, J ) 8.1, 2.1 Hz, 1H), 7.20 (d, J ) 8.1 Hz, 1H), 7.72 (d, J ) 2.1 Hz, 1H). 13C NMR (125 MHz, acetone-d6) δ 15.1, 34.5, 52.0, 55.3, 109.1, 125.9, 127.2, 128.7, 132.1, 132.6, 136.3, 164.0, 167.5. IR (thin film) ν (cm-1) 1640. HRMS (EI) calcd for C13H14ClNO2 251.0713 [M]+, found 251.0713. Azaspiro[4.5]decane Derivatives 32 and 33. These materials were obtained from PDC-mediated oxidative demetalation of complexes 31 and 28, respectively, using an experimental procedure described by Liebeskind.19e Products were isolated by radial chromatography (SiO2, EtOAc). Compound 32: 9 mg (14%); yellow solid, Rf ) 0.48 (EtOAc). 1H NMR (500 MHz, CDCl3) δ 1.87 (d, J ) 1.2 Hz, 3H), 2.49 (s, 3H), 2.93 (s, 3H), 3.22 (d, J ) 10.5 Hz, 1H), 3.26 (d, J ) 10.5 Hz, 1H), 3.53 (s, 3H), 6.15 (dd, J ) 1.6, 1.2 Hz, 1H), 6.23 (dd, J ) 9.8, 1.6 Hz, 1H), 6.78 (d, J ) 9.8 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 12.5, 19.8, 30.0, 46.8, 54.3, 54.4, 107.8, 126.7, 127.5, 151.5, 160.6, 163.8, 168.7, 186.9. IR (neat) ν (cm-1) 1677, 1659. HRMS (EI) calcd for C14H17NO3 247.1208 [M]+, found 247.1208. Compound 33: 3.0 mg (7%); yellow oil, Rf ) 0.44 (EtOAc). 1H NMR (500 MHz, CDCl3) δ 2.42 (s, 3H), 2.91 (s, 3H), 3.11 (d, J ) 9.5 Hz, 1H), 3.47 (d, J ) 9.5 Hz, 1H), 3.54 (s, 3H), 6.27-6.36 (m, 3H). 13C NMR (125 MHz, CDCl3) δ 12.2, 30.1, 52.2, 54.3, 56.5, 112.0, 122.8, 124.7, 142.4, 150.4, 161.9,

J. Org. Chem, Vol. 69, No. 4, 2004 1167

Pigge et al. 167.5, 199.5. IR (thin film) ν (cm-1) 1679, 1660. HRMS (EI) calcd for C13H14ClNO3 267.0662 [M]+, found 267.0654.

Acknowledgment. We thank the NIH-NIGMS for financial support (1R15GM63529-01).

1168 J. Org. Chem., Vol. 69, No. 4, 2004

Supporting Information Available: General experimental details, copies of 1H NMR spectra, and X-ray crystallographic data. This material is available free of charge via the Internet at http://pubs.acs.org. JO035058L