Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Rhodium-Catalyzed Enantioselective Alkenylation of Cyclic Ketimines: Synthesis of Multifunctional Chiral α,α-Disubstituted Allylic Amine Derivatives Yi Li,§,†,‡ Bo Liu,§,†,‡ and Ming-Hua Xu*,† †
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China ‡ University of Chinese Academy of Sciences, Beijing, 100049, China S Supporting Information *
ABSTRACT: By employing a simple open-chain chiral phosphite-olefin ligand, a highly enantioselective rhodium-catalyzed alkenylation of 1,2,5-thiadiazole 1,1-dioxide-type cyclic ketimines with diverse vinylboronic acids was achieved under mild conditions at room temperature. This protocol provides an efficient and practical access to multifunctional α,α-disubstituted chiral allylic amines bearing quaternary stereocenters in high yields (up to 99%) with good to excellent ee’s (up to 99%). Scheme 1. Enantioselective Construction of α,αDisubstituted Allylic Amines
hiral amines bearing an α-allyl functionality are of particular interest because they are exceptionally valuable building blocks in organic synthesis and have found wide application in medicinal chemistry and pharmaceutical industry.1 Over the past decades, considerable efforts have been devoted to their asymmetric synthesis.2−8 Accordingly, three main strategies have been developed to access chiral allylic amines (Scheme 1a), including transition-metal-catalyzed asymmetric allylic amination,3,4 asymmetric rearrangement of allylic imidates,5 and asymmetric addition of alkenyl nucleophiles to imines,6,7 which have proven to be powerful. However, despite these remarkable advances, convenient and efficient methods for the preparation of α,α-disubstituted allylic amines bearing a tetrasubstituted stereogenic center at the allylic position remain largely underdeveloped due to the significant synthetic challenges associated with the enantioselective installation of a quaternary carbon stereocenter. To date, there have been very few reports on the successful catalytic asymmetric construction of α,α-disubstituted chiral allylic amines. For example, Nguyen and Kleij have made great progress in asymmetric allylic amination using tertiary allylic imidates and substituted vinyl cyclic carbonates as rhodium/ palladium allyl precursors.4a,b Peters demonstrated that 3,3disubstituted allylic trifluoroacetimidates were capable of a highly enantioselective aza-Claisen rearrangement under the catalysis of planar-chiral pentaphenylferrocenyl palladacycles.5b,c Comparatively, transition-metal-catalyzed asymmetric addition of alkenyl nucleophiles to ketimines appears to be a simple and attractive strategy for straightforward access to chiral α,α-disubstituted allylic amines in terms of substrate
C
© XXXX American Chemical Society
availability. However, achieving high yield and enantioselectivity through the direct control of chiral catalysts still remains a very challenging task, and the problem is mainly attributed to Received: February 23, 2018
A
DOI: 10.1021/acs.orglett.8b00651 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters the intrinsic lower reactivity of ketimines and the inefficient enantiofacial differentiation. To our knowledge, few studies have been attempted so far, and only three single examples involving achieving high enantioselectivity through Rhcatalyzed asymmetric addition of alkenylboron reagents to keimines were reported by Hayashi,6e Lam,6f Kong and McLaughlin6g (Scheme 1b). Notably, an alternative route to chiral allylic amines bearing quaternary stereocenters was recently developed by Jia through nickel-catalyzed direct addition of styrenes to highly activated ketimines.7 Thus, there is an unmet need for highly efficient asymmetric approaches that could enable easy access to versatile α,αdisubstituted chiral allylic amine derivatives. In recent years, our group has focused on the development of effective chiral olefin ligands for asymmetric catalysis.9 In 2014, we reported the design of a new class of chiral phosphite-based open-chain olefin ligands10 and found they showed higher activity and enantioselectivity than sulfur-olefins in an asymmetric 1,2-addition of (E)-styrylboronic acids to sixmembered cyclic N-sulfonyl aldimines, allowing for the construction of α-monosubstituted allylic amine frameworks in an enantioselective manner.10a Motivated by this success, and in conjunction with our interest in this field, we became intrigued by the feasibility of their application in the more challenging enantioselective alkenylation of ketimines to access α,α-disubstituted allylic amines bearing quaternary stereogenic centers. Herein, we disclose our development of an exceptionally mild and convenient method that allows catalytic asymmetric addition of vinylboronic acids to 3-substituted-4aryl-1,2,5-thiadiazole 1,1-dioxides for synthesis of various highly enantioenriched thiadiazoline products. Such molecules containing a unique α,α-disubstituted allylic amine framework and sulfonamide functionality are of particular interest to organic chemists and pharmaceutical scientists,11 but there are no reports of their asymmetric synthesis via direct enantioselective catalysis. We initiated the work by evaluating simple open-chain chiral phosphite-olefin L1 as ligand for the reaction of 3-ethoxy-4phenyl-1,2,5-thiadiazole 1,1-dioxide (1a) and (E)-styrylboronic acid (2a) under the conditions of [Rh(COE)2Cl]2 (1.5 mol %) and aqueous K3PO4 (1 M) in toluene at room temperature. To our delight, the reaction proceeded smoothly and gave the expected alkenylation product 3aa in excellent yield (99%) with a promising enantioselectivity (83% ee) (Table 1, entry 1). This result suggested that simple chiral phosphite-olefin ligands could promote the reaction efficiently. Accordingly, to attain higher enantioselectivity, a variety of (R)-binol-derived phosphite-olefin L2−L9 that contained different aromatic moieties attached to the double bond were evaluated. It was found that the enantioselectivity was slightly improved with the introduction of a bulkier substituent onto the para-position of phenyl ring (L3−L4, entries 3−4). Further investigation revealed that L5−L6 bearing methoxy groups at the 3,5- or 3,4,5-position of the phenyl ring gave an obvious improvement in enantioselectivity, while maintaining the same excellent reactivity (entries 5−6). Changing the methoxy group in L5 to the sterically more bulky tert-butyl group exhibited the greatest preference, in terms of both catalytic activity and enantiocontrol (L7, 99% yield and 92% ee) (entry 7). In addition, ligands that contain large naphthyl groups at the terminal (L8, L9) or two methyl/phenyl substituents at the 3- and 3′-positions of the binaphthyl unit (L10, L11) were also prepared. Unfortunately, no superior results were obtained (entries 8−
Table 1. Optimization of Reaction Conditions for Alkenylation of 1a with 2aa
entry
L
additive
solvent
yield (%)b
ee (%)c
1 2 3 4 5 6 7 8 9 10 11 12 13
L1 L2 L3 L4 L5 L6 L7 L8 L9 L10 L11 L7 L7
K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K3PO4 K2HPO4
toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene DCE DCE
99 96 99 99 99 99 99 99 99 91 99 99 99
83 83 86 85 90 91 92 85 88 55 43 93 94
a Reactions were performed with 1a (0.1 mmol), 2a (0.2 mmol), [Rh(COE)2Cl]2 (1.5 mol %), L (3 mol %), and 1.0 equiv of additive (1.0 M) in 1 mL of dry solvent at room temperature. bIsolated yield. c Determined by chiral HPLC.
11). Following up on the encouraging results obtained with L7, effects related to the reaction solvent and additive were carefully examined (see Supporting Information (SI)). Finally, the combination of DCE and K2HPO4 was selected to be the optimal choice, giving the best result with 94% ee and 99% yield (entry 13). With the optimal conditions in hand, we sought to evaluate the scope and generality of the reaction. As summarized in Scheme 2, a variety of 3-substituted 4-aryl-1,2,5-thiadiazole 1,1dioxides (1) were all successfully reacted with (E)-styrylboronic acid (2a), providing the corresponding chiral thiadiazoline products (3) having an α,α-disubstituted allylic amine framework mostly in both high yields and enantioselectivities (up to 99% yield and 99% ee). In general, 4-phenyl-1,2,5-thiadiazole 1,1-dioxide species bearing different R substituents, such as ethoxyl, methoxyl, isopropoxy, and n-butylamino, at the 3position of cyclic ketimines were proven to be suitable substrates, as they all exhibited high reactivity and led to the formation of highly enantiomerically enriched products 3aa− 3da (92−96% ee). Furthermore, substrates with various metaand para-substituted functional groups in the Ar rings were well tolerated, affording the corresponding products 3ea−3ja with generally high enantioselectivities in excellent yields. In addition, the 2-naphthyl-substituted substrate also afforded the desired product (3ka) in very high yield (97%) and ee (97%). The electronic properties of the aromatic ring did not appear to affect the reaction yields and enantiomeric excess values. However, a large decrease in enantioselectivity was observed in the cases of cyclic ketimines bearing 1-naphthyl (3la) and 2-fluorophenyl (3ma), probably due to steric disadvantage. Notably, when ketimines containing a heteroB
DOI: 10.1021/acs.orglett.8b00651 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
line products (3eb, 3kb, 3ob, 3ec, 3jc, 3kc, 3nc, 3ed, and 3kd) in up to 99% yield with outstanding enantioselectivities (92− 97% ee). Remarkably, the reaction also tolerates vinylboronic acids with varied alkyl substituents, allowing access to various desired alkenylation products 3ee, 3ef, 3eg, 3oe, 3of, and 3og in good yields with the same high level of enantioselectivity (91−96% ee). These results suggest that significant variation of the olefin substituent has little effect on the reaction enantioselectivity. Thus, a broad range of sterically and electronically different vinylboronic acids could be employed with ease in this direct asymmetric alkenylation, indicating that this protocol is a promising method for constructing diverse chiral allylic amine frameworks bearing a tetrasubstituted stereogenic center. The absolute configuration of the alkenylation products was unambiguously established to be S by single-crystal X-ray analysis of 3ec (Figure 1).
Scheme 2. Rh/L7-Catalyzed Asymmetric Alkenylation of 1 with 2aa,b,c
a
The reaction was performed with 1 (0.1 mmol), 2a (0.2 mmol), [Rh(COE)2Cl]2 (1.5 mol %), L7 (3.0 mol %), and 1.0 equiv of K2HPO4 (1 M) in 1 mL of DCE at rt. bIsolated yield. cDetermined by chiral HPLC.
aromatic functionality such as thienyl and furanyl groups were used as the substrates, the alkenylation reactions proceeded equally well and afforded the desired products 3na−3pa in high yields with up to 99% ee. Subsequently, the scope with respect to the vinylboronic acids was examined to demonstrate the generality of this alkenylation (Scheme 3). Gratifyingly, reactions involving a variety of (E)-styrylboronic acids bearing either electrondonating or electron-withdrawing functional groups with a series of 3-ethoxy-4-aryl-1,2,5-thiadiazole 1,1-dioxides were all found to be successful, affording the expected chiral thiadiazo-
Figure 1. X-ray crystal structure of (S)-3ec.
To demonstrate the practicality of this protocol, a gram-scale reaction between ketimine 1a and vinylboron reagent 2a was carried out (see SI). Under the standard conditions, the reaction proceeded smoothly and gave 1.01 g of 3aa in equally high yield (98%) without loss of the enantioselectivity (94% ee). To further showcase the synthetic utility of this method, the transformations of alkenylation products 3aa and 3ba into a valuable vicinal diamine and α-aryl-β,γ-alkenyl α-amino amides were evaluated (Scheme 4). First, reduction of 3aa with NaBH4
Scheme 3. Rh/L7-Catalyzed Asymmetric Alkenylation of Vinylboronic Acid 2a,b,c
Scheme 4. Access to Enantioenriched Vicinal Diamine and β,γ-Alkenyl-α-Amino Amides
in THF at room temperature afforded the chiral cyclic sulfamide 4 in quantitative yield, and subsequent treatment of 4 with 1,3-diaminopropane led to the efficient formation of vicinal diamine 5 in 95% yield with untarnished ee (eq 1). Very gratifyingly, treatment of 3ba under melting conditions gave the corresponding sulfahydantoin 6 without losing optical purity.
a
The reaction was performed with 1 (0.1 mmol), 2 (0.2 mmol), [Rh(COE)2Cl]2 (1.5 mol %), L7 (3.0 mol %) and 1.0 equiv of K2HPO4 (1 M) in 1 mL of DCE at rt. bIsolated yield. cDetermined by chiral HPLC. dThe reaction was performed at 60 °C. C
DOI: 10.1021/acs.orglett.8b00651 Org. Lett. XXXX, XXX, XXX−XXX
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heterocycle sulfamide derivatives that possess great potential in drug discovery. We believe that this method will find wide application in organic synthesis and medicinal chemistry.
Further removal of the sulfonyl with LiAlH4 or ring cleavage with MeMgBr could lead to α-aryl-β,γ-alkenyl α-amino amides 7 and 8 in good yields, while maintaining the same level of enantioselectivity (eq 2). It is noteworthy that this kind of β,γunsaturated α-amino acid and their derivatives are important structural motifs presented in many biologically active natural products and pharmaceutical agents,12 and catalytic asymmetric approaches to access such quaternary-containing β,γ-unsaturated α-amino acid units remain considerably underdeveloped. Finally, the availability of the current methodology can also be featured by the intriguing synthetic transformations of the alkenylation product 3aa (Scheme 5). Treatment of 3aa with
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00651. Experimental procedures, characterization data, and copies of NMR and HPLC spectra (PDF) Accession Codes
Scheme 5. Transformations of Alkenylation Product 3aa
CCDC 1814140−1814141 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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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Ming-Hua Xu: 0000-0002-1692-2718 Author Contributions §
Y.L. and B.L. contributed equally.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank the National Natural Science Foundation of China (21472205, 81521005, 21502207, 21325209) and the Shanghai Municipal Committee of Science and Technology (15YF1414600) for financial support.
allyl bromide in the presence of K2CO3 in DMF at room temperature for 2 h, followed by the olefin metathesis using the second-generation Grubbs catalyst, afforded the dihydropyrrole derivative 9 in 90% yield for two steps. Similarly, treatment of 3aa with 3-bromopropyne, followed by cyclization under typical Pauson−Khand reaction conditions, efficiently delivered chiral quaternary carbon-containing fused cyclopenta[c]proline derivatives 10a and 10b in 34% and 47% yields without erosion of the ee. The stereochemistry of 10a and 10b were determined by X-ray crystallographic analysis and NOE experimentation (see SI), respectively. Furthermore, ammoniation of alkenylation product 3aa could also be conducted smoothly in the presence of ammonia or benzylamine to provide the corresponding products 11 and 12 in excellent yield without any loss of enantioselectivity. Interestingly, the proton signal indicated that CN of compound 11 is located outside the ring, which is different from the case in compound 12. In summary, we have developed an efficient protocol for the challenging asymmetric addition of alkenyl nucleophiles to ketimines. Under rhodium catalysis with a simple open-chain chiral phosphite-olefin as a ligand, the reaction of diverse vinylboronic acids with varied 3-substituted-4-aryl-1,2,5-thiadiazole 1,1-dioxides could proceed smoothly at room temperature, enabling reliable access to a broad range of functional α,α-disubstituted chiral allylic amines bearing quaternary stereocenters in high yields with good to excellent enantioselectivities (up to 99% ee). The method is promising and notable because it can be applied to access highly valuable enantioenriched β,γ-unsaturated α-amino amides and vicinal diamines with ease of removal of sulfonyl. Furthermore, the products can be easily transformed into a series of interesting
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REFERENCES
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DOI: 10.1021/acs.orglett.8b00651 Org. Lett. XXXX, XXX, XXX−XXX
