Letter Cite This: Org. Lett. 2019, 21, 473−475
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A Protocol for an Iodine−Metal Exchange Reaction on Cubane Using Lithium Organozincates Yumi Kato,† Craig M. Williams,‡ Masanobu Uchiyama,§,∥ and Seijiro Matsubara*,†
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†
Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyotodaigaku-Katsura, Nishikyo, Kyoto 615-8510, Japan ‡ School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, 4072, Queensland, Australia § University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan ∥ Cluster for Pioneering Research (CPR), Advanced Elements Chemistry Laboratory, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan S Supporting Information *
ABSTRACT: The iodine−metal exchange reaction on cubane was examined using various lithium organozincates. Among these, the dianionic zincate, n-Bu4ZnLi2, gave optimum results. The resulting cubyl metal species could be converted into various cubane derivatives via addition reactions with electrophiles, such as an organohalide or aldehyde. The potential functional group tolerance of organozincates lends this protocol to the synthesis of polyfunctionalized cubane derivatives. ince Eaton reported the first synthesis of a cubane derivative in 1964, this simple regular hexahedral skeleton has attracted attention as a novel hydrocarbon unit with reasonable stability.1 Within the cubane structure (pentacyclo[4.2.0.02,5.03,8.04,7]octane), the distance across the cube body diagonal (2.72 Å) is comparable to that of the benzene ring (2.79 Å). Eaton predicted that cubane could potentially be useful in pharmaceutical research as a benzene bioisostere.2 Although cubane has a high strain energy (161.5 kcal/mol), its kinetic stability is reasonable (with a decomposition temperature of >220 °C). The large barrier to ring opening arises from the absence of symmetry allowed pathways for achieving a concerted two-bond ring opening in the context of a thermal reaction. Compared to the extensive efforts that have been applied toward setting up substituents on benzene rings to obtain useful aromatic compounds, the corresponding transformations of cubane have room for development. Metalation of a cubane moiety is expected to provide a powerful approach to reactions with various electrophiles to obtain the corresponding substituted cubanes. The presence of ionic character at an atom adjacent to a cubane can often trigger ring opening via a stepwise mechanism;3 therefore, care must be taken when using a main-group metal reagent with Lewis acidity to functionalize substrates such as cubane carboxylic acid derivatives. The established method for obtaining functionalized cubyl amides involves a deprotonation protocol using Li-TMP. In this method, the corresponding directed ortho-lithiation of the cubyl amide affords the corresponding lithiated product in a small yield (3%) under equilibrium conditions. The addition of a metal salt, such as HgX2, MgX2, or ZnX2, in excess of LiTMP should yield the metalated compound.4 Cubyl iodide, which can be prepared via a radicalinitiated decarboxylative iodization method,5 can also be used as a cubyl metal precursor in a halogen−lithium exchange
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© 2019 American Chemical Society
protocol as reported by Senge,6 but some functionalized iodides cannot tolerate the presence of a strong organolithium reagent. Moreover, cubyllithium is not necessarily highly nucleophilic in reactions with some electrophiles, considering its thermal instability and high basicity. Thus, it is highly desirable to develop a novel protocol for forming cubyl metal species with high nucleophilicity via a selective halogen−metal exchange reaction besides halogen−lithim exchange. Under such circumstances, we focused on the use of a dianionic organozincate that has been applied successfully by Uchiyama7 to halogen−metal exchange of functionalized organic halides. We attempted to apply this protocol to certain functionalized iodocubane derivatives. To our delight, the dianionic zincates converted these derivatives into the corresponding metal species with reasonable nucleophilicity. As shown in Table 1, 4-iodocubane-N,N-diisopropylcarboxamide (1a X = I)8 was treated with various organometallic reagents and quenched with D2O. In the presence of alkyl lithium, the lithiated cubane formed a tertiary alkyl lithium that was so strongly basic that it was protonated by any proton source present. In the reaction shown in entry 1, THFd8 instead of the usual THF was used as the solvent. Quenching with H2O then gave 4 as a major product without 3, so the solvent THF did not act as a proton source. The basicity of the formed cubyllithium may be strong enough to react with 1-iodobutane, which formed as a result of the iodine−metal exchange reaction, to undergo an E2 reaction under the reaction conditions. By contrast, the dianionic zincates gave the deuterated product 3 in high efficiency via a serviceable metalated intermediate (entries 4 and 6). The Received: November 21, 2018 Published: January 10, 2019 473
DOI: 10.1021/acs.orglett.8b03721 Org. Lett. 2019, 21, 473−475
Letter
Organic Letters
nionic zincate 2d was treated with various electrophiles 5. Halides, aldehydes, and silylating reagents reacted to provide the corresponding adducts 6 with reasonable yields. In Scheme 1, 2-iodocubane-N,N-diisopropylcarboxamide (7) was also transformed into a cubylmetal species via
Table 1. Screening Reagents for the Metallation of 4Halocubane-N,N-diisopropylcarboxamide (1)a
entry
X
reagent
T (°C)
t (h)
3 (%)
4 (%)
1 (%)
1 2 3 4 5 6 7b 8 9 10
I I I I I I I Br Br Br
n-BuLi (2a) t-BuLi (2b) n-Bu3ZnLi (2c) n-Bu4ZnLi2 (2d) Me4ZnLi2 (2e) t-Bu4ZnLi2 (2f) n-Bu4ZnLi2 (2d) t-BuLi (2b) n-Bu4ZnLi2 (2d) t-Bu4ZnLi2 (2f)
0 0 25 25 25 25 25 0 60 60
0.5 0.5 2.0 2.0 2.0 2.0 2.0 1.0 2.0 2.0
4 9 72 >99 0 60 43 3 99
Scheme 1. Reaction of the Metalated Cubane Prepared from 2-Iodocubane-N,N-diisopropylcarboxamide (7)
metalation. In the case of the 2-iodo derivative, the dianionic zincate prepared from t-BuLi gave improved results. Treatment with allyl bromide (5b) gave the corresponding adduct 8 in reasonable yields. We attempted to obtain the more highly substituted cubanes selectively via a site-selective bromination reaction (Scheme 2). Treatment of 4-deuteriocubane-N,N-diisopropyl-
a
1 (0.1 mmol) and 2 (0.2 mmol) were used. b1 (0.1 mmol) and 2d (0.1 mmol) were used.
corresponding zincate prepared from methyllithium 2e did not work (entry 5). The use of 1.0 equiv of 2d resulted in a lower yield of 3 (entry 7). The superior performances of the dianionic zincates, prepared from n- and tert-butyllithium and dichlorozinc in the context of halogen−metal exchange on the cubane core, were clearly shown. Ionic lithium counterions contained within the zincate possess high Lewis acidity, due to the anionic species being surrounded by bulky hydrophobic alkyl groups. Therefore, the lithium cations would presumably coordinate to the iodine atom on the cubane to facilitate the transmetalation initiated by nucleophilic attack of a butyl anion.9Unfortunately, the corresponding bromide−metal exchange (1b, X = Br) did not give positive results (entries 8 and 9).10 As shown in Table 2, the metalated cubane prepared from 4iodocubane-N,N-diisopropylcarboxamide (1a) and the dia-
Scheme 2. Site-Selective Bromination of 3 with a Bulky Bromoamide
carboxamide (3), prepared as shown in Table 1, with the bulky N-bromoamide reported by Alexanian,11 gave 4deuterio-3,5-dibromocubane-N,N-diisopropylcarboxamide (9) in 70% yield accompanied by the slight formation of 4deuterio-3-bromocubane-N,N-diisopropylcarboxamide (16%) and 4-bromocubane-N,N-diisopropylcarboxamide (3%). The selectivity could be explained by the relatively stable C−D bond compared to C−H and the steric hindrance of the bromination reagent. This selective formation of the prochiral dibromide 9 would provide a route to the preparation of a chiral cubane12 by selective functionalization of a C−Br bond via desymmetrization.13 Thus, the use of dianionic zincate has opened a path toward obtaining a reactive cubylmetal species from the corresponding iodide. The method displayed functional group tolerance and selectivity and will contribute to the preparation of cubane derivatives with potential utility as novel bioactive compounds.
Table 2. Reactions of Metalated Cubane Prepared from 4Iodocubane-N,N-diisopropylcarboxamide (1a) and 2d with Various Electrophiles (5)a
entry
E+
t (h)
1 2 3 4 5
benzyl bromide (5a) allyl bromide (5b) benzaldehyde (5c) furfural (5d) cyanotrimethylsilane (5e)
12 18 14 12 12
compd (%) 47 95 66 70 67
(6a) (6b) (6c) (6d) (6e)
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a
1 (0.1 mmol), 2 (0.2 mmol), and 5 (0.5 mmol) were used.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b03721. Experimental procedures, characterization data, and copies of NMR spectra for all products (PDF) 474
DOI: 10.1021/acs.orglett.8b03721 Org. Lett. 2019, 21, 473−475
Letter
Organic Letters
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(12) Fokin, A. A.; Schreiner, P. R.; Berger, R.; Robinson, G. H.; Wei, P.; Campana, C. F. J. Am. Chem. Soc. 2006, 128, 5332−5333. (13) Treatment of the dibromide 9 with 2d under the conditions of entry 2 in Table 2 generated a complex mixture; treatment with 2f resulted in compete recovery of starting material.
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Masanobu Uchiyama: 0000-0001-6385-5944 Seijiro Matsubara: 0000-0001-8484-4574 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by JSPS KAKENHI Grant Number 15H05845 and 17K19120. C.M.W. thanks the Australian Research Council for a Future Fellowship award (Grant Number FT110100851).
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REFERENCES
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DOI: 10.1021/acs.orglett.8b03721 Org. Lett. 2019, 21, 473−475
