Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Catalytic Enantioselective Tautomerization of Metastable Enamines Jingjing Liu,‡ Xin Yang,‡ Zhijun Zuo, Jiang Nan, Yaoyu Wang, and Xinjun Luan* Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of the Ministry of Education, College of Chemistry & Materials Science, Northwest University, Xi’an 710127, China S Supporting Information *
ABSTRACT: The first example of catalytic enantioselective tautomerization of structurally labile but isolable enamines for accessing their chiral imine-tautomers is described. Kinetically stable enamine-based dibenzo[b,d]azepines were tautomerized by a simple chiral BINOL−phosphoric acid, providing a variety of seven-membered imine products bearing both central and axial stereogenic elements in good yields (up to 96%) with excellent enantio- and diastereoselectivities (up to 97% ee, >20:1 dr).
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an unique case of enantioselective tautomerization of a single enol that was stable in DCM at −70 °C in the presence of stoichiometric (−)-cinchonidine (Scheme 1A).8 In a recent
rototropic tautomerism, defined by one of its early investigators as “the addition of a proton at one molecular site and its removal from another”,1 is of practical and fundamental interest in chemistry and biology. In the field of chemical syntheses, it commonly involves the relocation of a proton and shifting of a double bond and is mainly associated with the interconversion of keto−enol and imine−enamine tautomeric pairs.2 Tautomerization of these basic building blocks, which might be catalyzed by bases or acids, has been widely employed for enabling numerous important reactions.3 Noteworthy, many asymmetric transformations have been realized through stereocontrolled C-protonation of prochiral enolates, which are referred to as the intermediates in the interconversion of keto−enol tautomers, by using stoichiometric or catalytic amounts of chiral agents.4 Notwithstanding these advances on the chemo- and enantioselective transfer of the smallest element of the Periodic Table, direct asymmetric control over tautomerization of metastable enols or enamines, for accessing their enantioenriched carbonyl-derived tautomers with chiral tertiary centers, has long been deemed a tough task. In particular, proofof-principle studies on catalytic enantioselective tautomerization remain elusive. In principle, enantioselective tautomerization is necessarily a kinetic process. In addition to the obvious risks of reversible proton-transfer toward various basic sites and racemization at the new stereocenter, the largest problem facing successful enantioselective tautomerization is that they tend to occur too rapidly to be imparted with high enantioselectivity. Consequently, the majority of reported enantioselective tautomerization processes were embraced as the stereodetermining step in some cascade reactions.5−7 The best confirmation of this deceptively simple reaction course would be the direct conversion of isolated enol-type molecules into their more stable tautomers. However, the small free energy difference between tautomers and the low barrier between them make it extremely difficult to study them in isolation. To the best of our knowledge, there are only two examples of enantioselective tautomerization studies on the mutable but isolable molecules.8,9 In 1997, Duhamel announced © XXXX American Chemical Society
Scheme 1. Enantioselective Tautomerization of Isolated Metastable Enols or Enamines
seminal work, Fehr succeeded in the enantioselective tautomerization of two sterically hindered enols that were spectroscopically characterized in THF/toluene at −78 °C.9 However, further attempts on its catalytic version, by slowly adding those enol solutions to a substoichiometric amount of chiral Lewis base (30 mol %), led to the formation of keto tautomers with modest Received: November 20, 2017
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DOI: 10.1021/acs.orglett.7b03605 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
Inspired by these primary observations, we performed studies on the catalytic enantioselective tautomerization of 3a with chiral BINOL−phosphoric acids12 (CPAs) under argon (Table 1). To
enantioselectivities (Scheme 1B). In this context, we present the first successful example of catalytic enantioselective tautomerization of labile but isolable molecules (Scheme 1C). This process allows tautomerization of a new family of solid-state enaminebased dibenzo[b,d]azepines into their chiral imine tautomers bearing both central and axial chiralities by using a BINOL− phosphoric acid catalyst. Thus, this reaction also represents the first well-defined example of enantioselective enamine−imine tautomerization. In the course of our prior studies on the Pd(II)-catalyzed [5 + 2] annulation of o-arylanilines with alkynes,10 a mechanistic probe revealed that racemic imines were generated by thermal-driven tautomerization of their enamine-form dibenzo[b,d]azepines, which could not survive under harsh conditions. Further results with this approach indicated that the desired enamines could be concomitantly formed with their imine tautomers, albeit with very low yields (20:1 dr for all the cases) and high enantioselectivities (72−97% ee). With respect to the aniline ring, a variety of substituents such as methyl (3b,j), isopropyl (3c), tertbutyl (3d,l−u), phenyl (3e), and methoxy (3f) groups, and electron-withdrawing groups such as fluoro (3g), trifluoromethyl (3h), and trifluoromethoxy (3i) groups were tolerated. Generally, substrates bearing electron-rich groups gave better performance, with enamine 3d showing the superior results of 95% yield and 97% ee for 4d. In contrast, substrate 3h that contains a strong electron-withdrawing group clearly reduced the reactivity (52% yield) and enantioselectivity (72% ee). Remarkably, an axially congested substrate 3j was compatible, albeit with relatively low ee (72%). The limitation of this process became apparent when enamine 3k was tested, and nearly no desired 4k was generated in the presence of chiral phosphoric acids. However, product 4k could be isolated in 95% yield when using acetic acid as the catalyst. This observation implied that the possible intermolecular
During the workup, it was found that weakly acidic silica gel could trigger tautomerization of 3a, to a certain extent, to give imine product 4a as a single diastereomer (Scheme 3a). Based on Scheme 3. Preliminary Studies on the Stability of 3a
the X-ray studies on 4a, it is believed that the unusually high chemical and conformational stabilities for such an imine, upon facile hydrolysis conditions, are mainly attributed to the greatly twisted seven-membered scaffold. Moreover, it is necessary to note that electron-rich 3a slowly decomposed to peroxide 5a with excellent diastereoselectivity (>20:1 dr) upon prolonged exposure to the air, and its structure was unambiguously assigned by X-ray analysis (Scheme 3b). Thus, special attention should be paid to manipulating these metastable enamines. B
DOI: 10.1021/acs.orglett.7b03605 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 4. Reaction Scope with Variants on the Biaryls
Scheme 5. Reaction Scope with Variants on the Alkynes
with excellent enantioselectivities (80−95% ee). Remarkably, tautomerization of these enamines led to the formation of diastereomerically pure imines 4a′−j′. Satisfactorily, substrate 3k′ bearing heterocyclic 3-thienyl groups underwent tautomerization smoothly, affording optically active 4k′ in 87% yield with 71% ee. When dialkylacetylenes were tested for synthesizing the enamine substrates, it was found to be extremely difficult to isolate those compounds in the pure form, due to the direct tautomerization and decomposition. As a result, a relatively electron-efficient enamine 3l′, which was prepared from an alkyl− aryl mixed alkyne, was employed to examine the reaction performance, and product 4l′ were obtained as a diastereomeric mixture (4:1 dr) in 56% yield with 50% ee (for the major diastereomer). Notably, this diastereoselectivity is similar to the previously reported thermal-driven method.10 Most of products 4 were obtained as a single diastereomer, and the relative stereochemistry was assigned by comparison with the previous data.10 Moreover, the absolute configuration of 4u was determined to be (S,Ra) by X-ray analysis of the major diastereomer (6umajor) from the reduction process (Scheme 6)
a
3.0 mmol scale. b1 mol % of CPA-1 was used. c10 mol % of HOAc was used to replace CPA-1. NA = not applicable.
interaction between phosphoric acid and the amino group of 3k might be blocked by the o-methyl group. With regard to the upper aryl ring, it can be substituted with many important functional groups such as methoxy (3l), fluoro (3m,t), chloro (3n,u), trifluoromethyl (3o), trifluoromethoxy (3p), ester (3q), cyano (3r), and nitro (3s), and the reactions proceeded smoothly to deliver the anticipated products 4l−u in high yields (82−95%) with excellent enantioselectivities (84−95% ee). Moreover, it is worth mentioning that sterically hindered substrate 3u behaved extremely well in the tautomerization process, leading to the formation of product 4u in 94% yield with 94% ee. To showcase the practicality of this protocol, a gram-scale reaction with 3d (1.20 g) was carried out, and product 4d was obtained without notable loss of reactivity (1.13 g, 94% yield) and enantioselectivity (95% ee). Subsequently, the reaction performance of 3d with 1.0 mol % of CPA-1 was evaluated, and the results revealed that the same level of enantioselectivity was maintained (96% ee), albeit with a lower yield of 4d (27%). We next turned our attention to study of the reaction scope by using enamine-formed dibenzo[b,d]azepines (3a′−l′) that were prepared from a variety of alkynes (Scheme 5). Regarding the symmetrical building blocks with aryl groups, diversified substituents such as methyl (3a′), methoxy (3b′), fluoro (3c′,h′,j′), chloro (3d′), trifluoromethyl (3e′), ester (3f′), phenyl (3g′), and cyano (3i′) groups were tolerable on the para- (3a′−f′), meta- (3g′−i′), or ortho-position (3j′) of the aromatic ring, and products 4a′−j′ were isolated in 52−95% yield
Scheme 6. Absolute Stereochemistry Assignment
and by analogy the same configuration was attributed to all other dibenzo[b,d]azepines 4. Notably, Re-face hydride attack toward the imine moiety induced complete inversion of biaryl axis from Ra to Sa to release the ring strain. On the basis of previous studies on enantioselective protonation by using chiral phosphoric acids and the bifunctional nature of CPA-1,5g,6c−e,12 we proposed a novel activation model in which CPA-1 would first activate the amino moiety of enamines 3 with the basic phosphoryl oxygen through hydrogen bonding C
DOI: 10.1021/acs.orglett.7b03605 Org. Lett. XXXX, XXX, XXX−XXX
Organic Letters
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and then position the hydroxyl species in close proximity to the electron-rich carbon atom of enamines 3 via a eight-membered cyclic transition state, delivering the proton in an enantioselective manner to generate their corresponding chiral imine tautomers 4 (Scheme 7). Moreover, this model supports the phenomenon
that CPA-1 without 3,3′-substituents exhibited higher reactivity, since it causes less steric repulsion toward the bulky tetra-arylsubstituted enamine. In summary, we have developed an unprecedented example of chiral BINOL−phosphoric acid-catalyzed enantioselective enamine−imine tautomerization of new dibenzo[b,d]azepines containing a labile enamine moiety, thus leading to a variety of enantiomerically enriched seven-membered N-heterocycles in their imine form, possessing a tertiary carbon stereogenic center and a biaryl axis with great enantio- and diastereoselectivities. This highly atom-economical process, to the best of our knowledge, represents the first successful example of transferring one class of kinetically stable enols or enols equivalents into their enantioenriched keto tautomers by using a catalytic enantioselective tautomerization strategy.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03605. Experimental procedures and spectral data (PDF) Accession Codes
CCDC 1555756−1555758 and 1584794 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/ cif, or by emailing
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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REFERENCES
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Scheme 7. Proposed Activation Model
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Letter
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Yaoyu Wang: 0000-0002-0800-7093 Xinjun Luan: 0000-0002-5692-0936 Author Contributions ‡
J.L. and X.Y. contributed equally.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by the NSFC (21672169), the Science and Technology Department of Shaanxi Province (2017KCT37), and the Education Department of Shaanxi Province (12JS113). D
DOI: 10.1021/acs.orglett.7b03605 Org. Lett. XXXX, XXX, XXX−XXX
