N-Silyl Protecting Groups for Labile Aziridines: Application toward the Synthesis of N-H Aziridinomitosenes Don L. Warner,*,† Amber M. Hibberd,† Monica Kalman,‡ Artis Klapars,‡ and Edwin Vedejs‡ Departments of Chemistry, Boise State UniVersity, Boise, Idaho 83725, and UniVersity of Michigan, Ann Arbor, Michigan 48109
deprotection in the presence of the activating pyrrole.1,2,4,5 The moderately successful deprotection of compounds 3, 4, and 5 (isolated yields of 35%,2 41%,1 and 65%,4,5 respectively) may partly be attributed to the common electron-withdrawing ester at carbon-10. In contrast, reductive detritylation of analogues 11 and 2, both of which contain carbon-10 in the correct methylene oxidation state, was unsuccessful. For example, deprotection of aziridinomitosene 2 (PG ) trityl) led to the formation of an amorphous precipitate and a mixture of decomposition products.2
[email protected] ReceiVed June 23, 2007
Hindered N-silylamines were examined for their utility to serve as protecting groups for the labile aziridine nitrogen found within the highly sensitive aziridinomitosene framework. tert-Butyldiphenylsilyl and modified tert-butyldiphenylsilyl groups were the most resistant to nitrogen-silicon bond cleavage under various reaction conditions and were thus employed in transformations relevant to aziridinomitosene synthesis. The N-silylaziridines 7a, 21a, and 21b underwent azomethine ylide cycloaddition and afforded, upon deprotection, the N-H aziridine 24 in 18-32% overall yield for the three steps. In the course of several synthesis projects in our laboratories, we have encountered the need to deprotect aziridines found within the labile aziridinomitosene skeleton, including the aziridinomitosene analogues 1 and 2.1,2 In both compounds, fusion of the aziridine ring to the tricyclic core enforces orbital overlap between the benzylic C-N aziridine bond and the aromatic π-system and thus renders the aziridine particularly prone to acid-catalyzed heterolytic bond cleavage. Consequently, the tendency of the aziridine ring to spontaneously ring-open and decompose has severely limited the use of many traditional protecting groups, including those based on the carbamate, trityl (Tr), and benzyl groups. Indeed, as far as we are aware, reductive detritylation3 of analogues 3-5 using triethyl- or triisopropylsilane and methanesulfonic acid (MsOH) serves as the only successful example of aziridinomitosene aziridine † ‡
Boise State University. University of Michigan.
(1) Kim, M.; Vedejs, E. J. Org. Chem. 2004, 69, 7262-7265. (2) Vedejs, E.; Naidu, B. N.; Klapars, A.; Warner, D. L.; Li, V. S.; Na, Y.; Kohn, H. J. Am. Chem. Soc. 2003, 125, 15796-15806. (3) Vedejs, E.; Klapars, A.; Warner, D. L.; Weiss, A. H. J. Org. Chem. 2001, 66, 7542-7546.
In the search for a suitable protecting group for highly labile aziridine rings, a silyl group stood out as the most promising, due in part to a lack of extramural reactivity and ease of removal.6 Even more importantly, typical deprotection conditions, usually tetrabutylammonium fluoride (TBAF), do not require acidic or electrophilic reagents that are incompatible with the sensitive aziridine ring found in aziridinomitosenes. Although there are several examples of N-silyl-protected aziridines7 and azirines8 reported in the literature, the most relevant study examines amines protected with the sterically demanding tertbutyldiphenylsilyl (TBDPS) group.9 We postulated that a similarly hindered N-silylaziridine might exhibit a decreased rate of acid-catalyzed hydrolysis and thus provide a practical solution for the protection/deprotection of the highly sensitive aziridinomitosenes. In order to be useful in the synthesis of an aziridinomitosene, a suitable silicon-based aziridine protecting group would need to survive the relatively demanding oxazolium salt/azomethine ylide cycloaddition sequence used to construct the tetracyclic core of the target molecules (Scheme 1).10 Specifically, the formation of the oxazolium salt 8 requires heating the iodide precursor 7 to 70 °C in acetonitrile for approximately 3 h in the presence of silver triflate. (4) Vedejs, E.; Little, J. J. Am. Chem. Soc. 2002, 124, 748-749. (5) Vedejs, E.; Little, J. D. J. Org. Chem. 2004, 69, 1794-1799. (6) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic Synthesis, 3rd ed.; John Wiley & Sons, Inc.: New York, 1999. (7) Leroy, J.; Cantacuzene, D.; Wakselman, C. Synthesis 1982, 313315. (8) Belloir, P. F.; Laurent, A.; Mison, P.; Bartnik, R.; Lesniak, S. Tetrahedron Lett. 1985, 26, 2637-2640. (9) Overman, L. E.; Okazaki, M. E.; Mishra, P. Tetrahedron Lett. 1986, 27, 4391-4394. (10) Vedejs, E.; Klapars, A.; Naidu, B. N.; Piotrowski, D. W.; Tucci, F. C. J. Am. Chem. Soc. 2000, 122, 5401-5402.
10.1021/jo7013615 CCC: $37.00 © 2007 American Chemical Society
Published on Web 10/02/2007
J. Org. Chem. 2007, 72, 8519-8522
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Although not always problematic, the Lewis acidic silver cation has been shown to deleteriously coordinate to the aziridine nitrogen, resulting in a decreased yield for some substrates.2 Moreover, the silane protecting group must also endure a nucleophilic environment as the tetracycle 9 is generated by treating the oxazolium salt 8 with benzyltrimethylammonium cyanide. Thus, in addition to being stable under acidic conditions, a suitable protecting group must also resist nucleophilemediated decomposition. Due to the reported stability of hindered primary silyl ethers in basic and acidic methanol solutions,11 initial efforts focused on substrates 7a and 7b, where the aziridine is protected with the bulky tert-butyldiphenylsilyl (TBDPS) or triisopropylsilyl (TIPS) groups. The N-silylaziridine 7a was prepared by reductive deprotection of the corresponding N-tritylaziridine2 followed by treatment with TBDPS triflate obtained from tert-butyltriphenylsilane and triflic acid.12,13 If commercially available TBDPS chloride was used instead of the triflate, the reaction was impractically slow (no reaction, ca. 2 days). Upon purification, 7a underwent significant decomposition on silica gel, but addition of NEt3 to the eluting solvent alleviated this problem. The preparation of 7b was uneventful, with commercially available TIPS-triflate cleanly reacting with the N-H aziridine 6 to form the desired product, which was also purified on triethylamine-buffered silica gel in order to prevent decomposition. Once in hand, the two substrates were subjected to the oxazolium salt/azomethine ylide cycloaddition sequence. The silver triflate-promoted intramolecular alkylation of the oxazole nitrogen in 7a was accompanied by some cleavage (ca. 10%) of the silyl protecting group, as indicated by the NMR spectrum of the crude oxazolium salt 8a. The lability of the silyl protecting group was probably reflected in the relatively low yield (41%) of the cylcoadduct 9a isolated after treatment with BnMe3N+CN-. The same transformation for the N-TIPS analogue 7b produced the tetracycle 9b in approximately 19% yield. For comparative purposes, the cycloaddition for the corresponding N-tritylaziridine proceeds in yields ranging from 70 to 80%.2 Although the azomethine ylide cycloaddition of both 7a and 7b afforded product, the diminished yields demonstrated that while the TBDPS group was somewhat adequate, the TIPS group was completely unacceptable as a protecting group for the aziridine nitrogen in these systems. Furthermore, the lability (11) Davies, J. S.; Higginbotham, C. L.; Tremeer, E. J.; Brown, C.; Treadgold, R. C. J. Chem. Soc., Perkin Trans. 1992, 1, 3043-8. (12) Bassindale, A. R.; Stout, T. J. Organomet. Chem. 1984, 271, C1C3. (13) Vloon, W. J.; Vandenbos, J. C.; Willard, N. P.; Koomen, G. J.; Pandit, U. K. Recl. TraV. Chim. Pays-Bas 1991, 110, 414-419.
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of the N-TBDPS-protected intermediates would potentially present handling and purification problems earlier in the synthesis. Therefore, other hindered silyl triflates were prepared in order to assess their potential as protecting groups for nitrogen. Tri-tert-butylsilyl triflate (10a) was prepared from tritert-butylsilane and triflic acid.14,15 Unfortunately, protection of aziridines and even simple amines failed under all conditions tested, including a reaction with a lithiated amine. Similarly, silane 10b16 was not reactive enough to protect aziridine 6. Although protection of aziridines was readily accomplished using the less hindered silanes 10c,17 11,18 and 12,19 the resulting N-silylaziridines were less stable than the corresponding TBDPS derivatives. Surprisingly, dimesitylphenylsilyl-protected amines underwent instantaneous decomposition on unbuffered silica gel, whereas the TBDPS-protected amines required approximately 15 min for similar levels of degradation. The electron-rich mesityl groups are presumably partly responsible for the rapid decomposition of these highly hindered silyl-amines. A study conducted by Bassindale, Eaborn, and Walton suggests a mechanism for solvolysis where the neutral N-silylamine is in rapid equilibrium with its protonated form and nucleophilic attack at the silicon atom in this charged species is the rate-determining step.20 Because both the basicity of the nitrogen atom and steric hindrance at silicon are important contributors to the rate of N-silylamine solvolysis, we rationalized that addition of trifluoromethyl groups to the TBDPS protecting group would attenuate the acid-catalyzed solvolysis and provide increased stability by rendering the nitrogen atom less basic. Initial studies demonstrated that placement of the trifluoromethyl groups in the meta position offered slight stability advantages over placement at the para position, and accordingly, the trifluoromethyl TBDPS analogues 13 and 14 were constructed and used to protect benzylamine in order to evaluate the protecting group (Scheme 2). The synthesis of silyl triflate 13 was accomplished by treating 3-lithiobenzotrifluoride with tBuSiCl3 and then adding triflic acid to the silane 15. In the case of silyl triflate 14, tBuPhSiCl2 was used in place of the tBuSiCl3 since ipso substitution of the phenyl group in silane 16 with triflic acid was facile. In comparison, tris(3,5-bis(CF3)phenyl)tBuSi was inert to silyl triflate formation, even upon refluxing the silane and triflic acid in 1,2-dichloroethane. Although the silyl triflates could be (14) Wiberg, N.; Amelunxen, K.; Lerner, H. W.; Schuster, H.; Noth, H.; Krossing, I.; Schmidt-Amelunxen, M.; Seifert, T. J. Organomet. Chem. 1997, 542, 1-18. (15) Wiberg, N.; Schuster, H. Chem. Ber. 1991, 124, 93-95. (16) Wiberg, N.; Blank, T.; Lerner, H.-W.; Noeth, H.; Habereder, T.; Fenske, D. Z. Naturforsch., B. Chem. Sci. 2001, 56, 652-658. (17) Barton, T. J.; Tully, C. R. J. Org. Chem. 1978, 43, 3649-53. (18) Weidenbruch, M.; Schaefer, A.; Rankers, R. J. Organomet. Chem. 1980, 195, 171-84. (19) Lapkin, I. I.; Rogozhnikova, I. S.; Zhukov, M. A. Zh. Obshch. Khim. 1973, 43, 1739-41. (20) Bassindale, A. R.; Eaborn, C.; Walton, D. R. M. J. Organomet. Chem. 1970, 25, 57-67.
SCHEME 2
TABLE 1. Stability of N-Silyl Benzylamines to Assorted Conditions recoverya (%) conditions MeO2CCl MeI Ac2O 1:4 H2O/THF NaBH4, EtOH nBuLi LDA 20% KOH/MeOH, reflux, 16 h 1% NaOH/MeOH, rt, 1 h CD3OD
17
18
19
95 93 97 86 97 99 99 0 91 22%b (7 days)
93 93 95 94 98 86 89 0 78 9%b (8 days)
89 97 99 88 82 95 95 83 22%b (7.5 h)
a Isolated yield following silica gel purification. b Percent solvolysis determined by integration of benzylic protons in 1H NMR spectrum.
generated and stored on large scale, we found it more convenient to prepare the triflate for immediate use. This method was used to protect benzylamine, which gave the N-silyl amines 17 and 18 in 81% and 75% yield, respectively. The N-TBDPS benzylamine 19 was prepared in 98% yield from TBDPS-Cl in order to serve as a basis for comparison in stability studies. Initial insight into the stability of amines protected with 13 and 14 was obtained upon purification of the benzylamines 1719. 2-D thin layer chromatography studies indicated that 17 and 18 were both reasonably stable on unbuffered silica gels minimal decomposition occurred after 15 min of exposure. Furthermore, as a result of the enhanced stability, purification of 18 could be accomplished without addition of NEt3 to the eluting solvent. In contrast to 17 and 18, the N-TBDPS amine 19 was completely unstable on unbuffered silica gel with complete decomposition occurring in minutes. In order to evaluate the stability of the silyl amines beyond purification, compounds 17-19 were subjected to various reaction conditions (Table 1) analogous to those previously reported for an N-TBDPS amine.9 For example, all were stable to reactive alkylating and acylating reagents (MeI, methyl chloroformate, and acetic anhydride all with added NEt3 or NEtiPr2), and recovery of all three silyl amines was slightly lower after exposure to aqueous THF solutions for 6 h at rt. The TBDPS-benzylamine 19 was isolated in only 82% yield when treated with ethanolic NaBH4 while, on the other hand, the trifluoromethyl-TBDPS analogues 17 and 18 were recovered in 97-98% yield under the same conditions. The lability of 19 in protic solvents was also apparent in solvolytic studies conducted in deuterated methanol as the trifluoromethyl and
bis-trifluoromethyl analogues 17 and 18 exhibited 22% and 9% solvolysis after 7 and 8 days, respectively, and 19 underwent 22% methanolysis within 8 h at room temperature. Clearly, the electron-withdrawing trifluoromethyl groups provide extra stability in protic media. Ultimately, the CF3 derivatives 17 and 18 displayed similar or enhanced stability over the TBDPS analogue 19 in all but two reactions. The first involves the bis-CF3 derivative 18 in the presence of the strong bases LDA or nBuLi. In the case of 18, some decomposition took place, as a small amount of a silane-containing side product was isolated. However, decomposition was minimal and 18 was recovered in 86-89% yield, while 17 and 19 were obtained in greater than 95% yield. The second set of reaction conditions under which the TBDPS group was more stable than its fluorinated counterparts was encountered when the silyl amines were refluxed for 16 h in 20% KOH/methanol solutions. The TBDPS group was resistant to these conditions, and 19 was recovered in 83% yield. Compounds 17 and 18, however, did not survive and in both cases the silyl group was cleaved to yield the corresponding silanol. The electron-withdrawing trifluoromethyl groups presumably render the silicon atom more susceptible to nucleophilemediated silicon-nitrogen bond cleavage. Although unstable to the refluxing KOH/methanol solutions, 17 and 18 were recovered in 91% and 78% yield, respectively, when treated with a 1% NaOH/MeOH solution for 1 h at room temperature. We have used these conditions to remove an acetate protecting group from a secondary alcohol,10 indicating that the silanes have the potential to serve as orthogonal protecting groups under carefully chosen reaction conditions. The decomposition of silyl amines 17 and 18 under nucleophilic conditions suggested that additional hindrance about the silicon atom would increase the overall stability of the protected amines and prompted the attempted synthesis of the otrifluoromethyl TBDPS analogue 20. However, this potentially useful protecting group has thus far been unattainable.21
The question as to whether aziridines protected with 13 and 14 would survive the Lewis acidic conditions of the AgOTf/ oxazolium salt forming reaction and the nucleophilic conditions of the cyanide/azomethine ylide cycloaddition reaction remained to be answered. The experiments with the alkylating and acylating reagents as well as the experiments in protic conditions suggested that the silyl aziridine would offer increased stability during the AgOTf-promoted oxazolium salt-forming reaction. On the other hand, the decomposition observed when the silyl amines were exposed to basic/nucleophilic conditions suggested that the cyanide-mediated cycloaddition sequence might be problematic. Furthermore, it was still unclear if the new protecting groups could be removed under the mild conditions mandated by the highly reactive tetracyclic aziridinomitosene skeleton. In order to address these issues, aziridine 6 was protected with 13 and 14 (Scheme 3). (21) The precursor to 20, tert-butyl(phenyl)bis(2-(trifluoromethyl)phenyl)silane, was synthesized from tBuPhSiF2, but this compound provided only unidentifiable products unpon treatment with triflic acid.
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the benefits of the increased acid stability are offset by the silicon atom’s increased electrophilicity and corresponding susceptibility toward nucleophilic attack. As a result of their enhanced stability, we envision that hindered silanes bearing electron-deficient substituents will be useful as blocking groups for sensitive amines requiring careful consideration of protecting group removal. Experimental Section
The oxazolium salts 22a and 22b were formed upon heating the silyl aziridines 21a and 21b to 70 °C in CH3CN in the presence of AgOTf. The 1H NMR spectra of the crude products showed that minimal cleavage of the silane protecting groups had occurred, demonstrating the increased stability of the new protecting groups to the Lewis acidic conditions. On the other hand, increased reactivity toward nucleophiles was observed upon addition of 22a and 22b to benzyltrimethylammonium cyanide since the overall yield of 23a was decreased if the reaction mixture was stirred for more than 15 min at room temperature. In contrast, if stirring time was kept to ∼15 min, the yield improved significantly to 52% of approximately 95% pure 23a. Removal of the N-silyl protecting group was accomplished by treating 23a with TBAF at 0 °C for 15 min, providing pure deprotected 24 in 32% overall yield from the iodide 21a. Repeating the reaction sequence with 21b did not progress with the same degree of success, since the N-H aziridine 24 was isolated in only 18% overall yield for the three steps. The 1H NMR spectrum of the oxazolium salt 22b displayed minimal decomposition, suggesting that the Lewis acidic silver cation had minimal influence on the decreased yield. Thus, the decreased yield is presumably the result of the increased electrophilicity of the silanesinduced by the additional trifluoromethyl groupssto the nucleophilic cyanide. The same series of reactions for the TBDPS-protected analogue 7a produced the deprotected 24 in 26% overall yield. As far as we know, these are the only successful examples of aziridine deprotection in the aziridinomitosene series with substrates that have the C(10) carbon in the correct oxidation state. In summary, the silicon-based protecting groups examined herein provided access to the highly unstable N-H aziridines contained within the aziridinomitosene framework. For the sensitive aziridines, TBDPS derivatives proved to be most stable to the demanding reaction conditions. The addition of electronwithdrawing trifluoromethyl groups to the phenyl rings of TBDPS offered extra stability by serving to decrease the basicity of the aziridine nitrogen atom. The decrease in basicity was valuable in the Lewis acidic silver cation oxazolium salt reaction and presumably resulted in a modest yield increase for the cycloaddition reaction. However, based upon the results of reactions in the presence of hydroxide and cyanide, some of
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Representative Procedure: Synthesis of Silanes. Synthesis of Bis(3,5-bis(trifluoromethyl)phenyl)(tert-butyl)(phenyl)silane (16). A solution of 1-bromo-3,5-bis(trifluoromethyl)benzene (3.78 mL, 21.91 mmol) in 50 mL of ether was cooled to -120 °C (liquid N2/pentane), and tBuLi (1.4 M solution in pentane, 31.3 mL, 43.4 mmol) was added dropwise over 30 min. After stirring at -120 °C for another 10 min, tBuPhSiCl2 (2.2 mL, 10.43 mmol) was added dropwise. Dry ice was added to the cold bath, and the reaction was allowed to slowly warm to rt. After the mixture was stirred for 24 h, 25 mL of ice-water was added to the now black solution, which was extracted with ether, dried (MgSO4), concentrated, and purified via flash column chromatography on silica gel (hexanes) to yield 5.498 g (90%) of 16 as a clear colorless oil: HRMS calcd for C22H11F12Si 531.0438, found (EI) m/z ) 531.0415, error ) 4 ppm (M - C4H9+); IR (neat, cm-1) 1615, aromatic CdC; 1H NMR (400 MHz, CDCl3, ppm) δ 7.97 (6H, s) 7.55-7.42 (5H, m) 1.23 (9H, s); 13C NMR (100 MHz, CDCl3, ppm) δ 137.2, 136.3, 136 (m), 131.5 (q, 2JCF ) 33.1 Hz), 131.0, 130.7, 128.9, 124.1 (heptet, 3J 1 CF ) 3.8 Hz), 123.5 (q, JCF ) 272.6 Hz), 28.6, 18.9. Representative Procedure: Synthesis of N-Silylamines and -aziridines. Synthesis of N-Benzylbis(3,5-bis(trifluoromethyl)phenyl)(tert-butyl)silanamine (18). To silane 16 (945 mg, 1.605 mmol) in 10 mL of CH2Cl2 at 0 °C was added TfOH (0.142 mL, 1.605 mmol) dropwise. After 3 h at 0 °C, the solution was transferred via cannula to benzylamine (0.159 mL, 1.459 mmol) and NEt3 (0.492 mL, 3.53 mmol) in 2 mL of CH2Cl2 at 0 °C. After being stirred at 0 °C for 30 min and at rt for 30 min, the solution was poured into 10 mL of H2O, extracted with ether, dried (MgSO4), and concentrated. The resulting brown oil was purified via flash column chromatography on silica gel (60:1 hexane/ether eluent) to yield 0.674 g (75%) of 18 as a clear colorless oil: HRMS calcd for C27H23F12NSi 618.1486, found (ESI) m/z ) 618.1483, error 0.5 ppm (M + H+); IR (neat, cm-1) 1615, aromatic CdC; 1H NMR (300 MHz, CDCl3, ppm) δ 8.11-8.06 (4H, m) 7.96 (2H, s) 7.347.15 (5H, m) 3.87 (2H, d, J) 7.6 Hz) 1.59 (1H, t, J) 7.6 Hz) 1.07 (9H, s); 13C NMR (100 MHz, CDCl3, ppm) δ 141.8, 137.0, 135.3, 131.3 (q, 2JCF ) 32.6 Hz), 128.7, 127.2, 126.9, 123.9 (m), 123.5 (1JCF, J ) 271.6 Hz), 46.5, 27.0, 18.3.
Acknowledgment. The work described in this paper was supported in part by the National Institutes of Health (Grant Nos. CA17918 and CA11346), the Mountain States Tumor and Medical Research Institute (Small Project Grant), and Boise State University. Supporting Information Available: Stability studies of N-silyl benzylamines. Preparation and characterization of 6, 7a, 9, 15, 17, 19, 21a,b, and 24. 1H NMR spectra for all new compounds. This material is available free of charge via the Internet at http: //pubs.acs.org. JO7013615
