Letter pubs.acs.org/OrgLett
3‑Methylene-4-amido-1,2-diazetidine as a Formal 1,4-Dipole Precursor: Lewis Acid-Catalyzed Nucleophilic Addition with Silylated Nucleophiles Takashi Okitsu,* Keiko Kobayashi, Ryosuke Kan, Yuji Yoshida, Yuki Matsui, and Akimori Wada Department of Organic Chemistry for Life Sciences, Kobe Pharmaceutical University, 4-19-1, Motoyamakita-machi, Higashinada-ku, Kobe 658-8558, Japan S Supporting Information *
ABSTRACT: 3-Methylene-4-amido-1,2-diazetidine (MADA) was prepared for the first time via formal [2 + 2] cycloaddition of an allenamide and an azodicarboxylate. MADA worked as a formal 1,4-dipole precursor toward nucleophilic addition with various silyl enol ethers and allyltrimethylsilanes.
D
onor−acceptor (D−A) cyclopropanes1 and cyclobutanes2 are valuable synthons as formal 1,3- and 1,4-dipoles toward cycloadditions and nucleophilic additions because those rings are easily cleaved at the C−C bond between the donor-C atom and the acceptor-C atom due to the high ring strain and polarization (Scheme 1A). In recent years, Matsuo3 and Waser4 have elegantly explored the utility of D−A cyclobutanes as 1,4-dipole
surrogates. With analogous examples of azetidines, fourmembered rings containing a nitrogen atom, 1,4-dipole surrogates have been also well-known.5 However, to the best of our knowledge, the use of 1,2-diazetidines for formal 1,4dipole precursors has not been previously reported except for their acid hydrolysis.6 Allenamides are highly useful synthetic units because we can predict their reactions with electrophiles at the β-carbon of an allene having moderate nucleophilic properties.7 Above all, Hsung has pioneered the usage of allenamides for the synthesis of complex molecules. Especially, Hsung and colleagues have found that nitrogen-stabilized oxyallyl cations, formed by an oxidation of allenamides by dimethyl dioxirane, followed by the ringopening reaction of the allenoxides, behaved as 1,3-dipoles toward intramolecular [4 + 3] and [3 + 2] cycloadditions with dienes and ketones in the same molecules to create unique polycyclic skeletons (Scheme 1B).8 We hypothesized that a formal [2 + 2] cycloaddition of allenamide and azodicarboxylate would provide 3-methylene-4-amido-1,2-diazetidine (MADA), and the four-membered ring may cause a heterolysis between the donor-C atom and the acceptor-N atom to form a nitrogenstabilized azaallyl cation as a new type of 1,4-dipole (Scheme 1C). In this Letter, we show the potential of MADA as the formal 1,4-dipole precursor toward nucleophilic addition. To prove our methodology, we tried the preparation of MADA (2) by the formal [2 + 2] cycloaddition of allenamide 1 with diisopropyl azodicarboxylate (DIAD) in CH2Cl2 at room temperature, and as a result, 2 could be isolated, albeit a small amount of an enal 3 was present as a contaminant (Scheme 2A).
Scheme 1. 1,3- and 1,4-Dipoles
Received: July 19, 2017 Published: August 15, 2017 © 2017 American Chemical Society
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DOI: 10.1021/acs.orglett.7b02194 Org. Lett. 2017, 19, 4592−4595
Letter
Organic Letters Scheme 3. Scope of Nucleophilesa
Scheme 2. Formation and Reactivity of MADA (2)
The structure of 2 was fully assigned by 2D NMR (for more details, see the Supporting Information). Therefore, the formal [2 + 2] cycloaddition occurred at the α,β-double bond of the allenamide 1.9,10 Enal 3 would be formed by hydrolysis of 2 due to the contamination of water and deuterium chloride in CDCl3. This experimental observation indicated that heterolytic cleavage of 2 occurred at an aminal position in the presence of a Lewis acid and that the subsequent nucleophilic addition of water toward nitrogen-stabilized azaallyl cation A would proceed (Scheme 2B). Thus, we exposed 1 to DIAD followed by aqueous HCl solution at room temperature without isolation of 2 to provide 3 in 49% yield. Furthermore, the C−C bond forming reaction was also acceptable when in situ prepared 2 was employed with silyl enol ether 4a as the nucleophile and a catalytic amount of trimethylsilyl trifluoromethanesulfonate (TMSOTf) as the Lewis acid at −78 °C in a one-pot operation, leading to conjugate adduct 5a in 85% yield. Notably, these reactions proceeded in high regio- and stereoselective manners: while water as a hard nucleophile reacted at the iminium carbon of A, the soft nucleophile 4a reacted at the terminal methylene site. In addition, 5a was obtained as the Z-form only. MADA (2) behaved as the formal 1,4-dipole precursor toward nucleophilic addition. These results prompted us to examine the generality of the reaction with various nucleophiles (Scheme 3). Not only six-membered silyl enol ether 4b but also the conjugated variants 4c−d were applicable to TMSOTf-catalyzed nucleophilic addition to afford enehydrazides 5a−d in good yields. In the case of 4d as the nucleophile, direct adduct 5d′ was also obtained in 19% yield, probably due to its less-hindered nucleophilic site. Interestingly, cyclic hemiaminal 5e was afforded in 66% yield by the reaction with 4e prepared from isobutyraldehyde. To our delight, allylsilanes 4f−m were also suitable nucleophiles for the conjugate addition toward 2. The substituent at the β-position of the allylsilane did not affect the reaction: not only Csp3-, Csp2-, and Csp-substituted allylsilanes 4g−i but also ester and bromo-containing compounds 4j−k participated in formation of conjugate adducts 5f−k, respectively, in high yields. Cyclic allylsilanes 4l−m permitted this allylation to provide exo- and internal olefins 5l−m. Moreover, allenylsilanes 4n−o functioned as good nucleophiles for this reaction to afford alkynes 5n−o. Notably, all products 5a−o were obtained as only Z-stereoisomers.
a
Conditions: 1 (1 equiv), DIAD (3 equiv), 4a−o (3 equiv), TMSOTf (20 mol %), CH2Cl2 (0.5 M). Isolated yields are listed.
Other azodicarboxylates such as methyl and ethyl congeners instead of DIAD were applicable to allylation of MADA (Scheme 4). Notably, a removal of hydrazide was achieved by the reaction Scheme 4. Scope of Azodicarboxylates
of Troc-substituted enehydrazide 5r, obtained from the reaction with bis(2,2,2-trichloroethyl) azodicarboxylate, with activated zinc dust in AcOH to produce ketone 6. With the general procedure for nucleophilic addition of MADA (2) in hand, we next conducted an investigation of the scope of allenamides (Scheme 5). In this exploration, allylsilane 4f was used for the nucleophile. For the amide part, cyclic and 4593
DOI: 10.1021/acs.orglett.7b02194 Org. Lett. 2017, 19, 4592−4595
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Organic Letters Scheme 5. Scope of Allenamidesa
acyclic carbamates 7a−b, sulfonamides 7c−d, imidazolidinone 7e, and lactam 7f all underwent reaction to afford 8a−f in moderate to good yields with complete Z-selectivity. Under these conditions, the acid-sensitive Boc group of 7b was tolerated well. Allylation of allenamde 7g, which contains n-propyl group at γposition of allene, produced conjugate adduct 8g in 44% yield accompanied by less amount of direct adduct 8g′. These results showed the conjugate addition toward azaallyl cation A′ would be partially inhibited by n-propyl group. On the basis of the outcomes of these reactions, we proposed two reaction mechanisms as shown in Scheme 6. In the first step of the formation of MADA (2), a formal [2 + 2] cycloaddition could occur by either a stepwise reaction or by a concerted one. The second step of nucleophilic addition toward MADA could also occur through two possible pathways. For path A, a ringopening reaction of TMSOTf-activated MADA forms a nitrogen-stabilized azaallyl cation A. Subsequent nucleophilic conjugate addition toward A would proceed via s-trans-form rather than the s-cis-form due to the steric hindrance between an oxazolidinone ring of A and a nucleophile. As a result, the Z-form of silylated hydrazide B might be generated, and the aqueous workup resulted in (Z)-5. For an alternative mechanism (path B), ring-opening and nucleophilic addition occur in a concerted manner. We proposed two transition states: the inward rotation of oxazolidinone (TS-1) and an outward one (TS-2).11 The TS2 that affords (E)-B might be disfavored due to a steric repulsion between the oxazolidinone and the exo-methylene site. However, TS-1 is thought to be favored because the oxazolidinone rotates toward the hydrazide that is disconnected at the C−N bond resulting in the Z-form of 5 via (Z)-B. The nucleophilic adducts of MADA could be further transformed into other compounds (Scheme 7). For example, N-Boc enamide 8b was allowed to hydrolyze in acidic solution to
a
Conditions: 1 (1 equiv), DIAD (3 equiv), 4f (3 equiv), TMSOTf (20 mol %), CH2Cl2 (0.5 M). Isolated yields are listed. bAllenamide 7e was treated with DIAD for 24 h.
Scheme 6. Plausible Reaction Mechanism
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Organic Letters
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Scheme 7. Transformation of 8b, 5g, and 5k
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02194. Experimental procedures and full characterization of all compounds (PDF)
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REFERENCES
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afford α-hydrazido aldehyde 9. Various alkene units introduced by allylation were useful precursors for hydrazide-containing sixmembered ring formations: intramolecular hydroamination of 5g and copper-catalyzed C−N coupling12 of 5k provided pyridazine derivatives 10 and 11, respectively, in good yields. Those cyclized products might not be accessible by other classical methods. In conclusion, we have developed a donor−acceptor 1,2diazetidine, termed MADA, for a new 1,4-dipole precursor and have applied it to TMSOTf-catalyzed nucleophilic addition. A wide range of nucleophiles 4a−o was applicable to a regioselective nucleophilic addition in a Z-selective manner. In addition, various types of MADA were prepared by formal [2 + 2] cycloaddition of allenamides and DIAD were available for nucleophilic addition in all cases. A wide variety of applications using MADA, elucidation of the mechanism for Z-selectivity on the nucleophilic addition, and application of products for peptidomimetics as azapeptides13 are ongoing.
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Letter
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Takashi Okitsu: 0000-0001-5836-4470 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was partially supported by JSPS KAKENHI Grant Number 15K07878 (T.O.). We thank Ms. A. Yoshida (Kobe Pharmaceutical University) and Ms. Y. Ohnishi (Kobe Pharmaceutical University) for the help with the experiments. 4595
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