Letter pubs.acs.org/OrgLett
Enantioselective N‑Heterocyclic Carbene Catalyzed Synthesis of Functionalized Indenes Changhe Zhang and David W. Lupton* School of Chemistry, Monash University, Clayton 3800, Victoria, Australia S Supporting Information *
ABSTRACT: An enantioselective NHC (N-heterocyclic carbene) catalyzed synthesis of indenes from bifunctional α,βunsaturated acyl fluorides and TMS enol ethers has been discovered. The reaction has broad generality (31 examples) and proceeds with high levels of enantioselectivity (most >92:8 er). Mechanistically the reaction likely occurs via a Michael/βlactonization/decarboxylation sequence. Derivatization studies and limitations are discussed.
O
Scheme 1. Background and Reaction Design
ver the past 10 years N-heterocyclic carbene (NHC) catalysis1 via the α,β-unsaturated acyl azolium (1) has played an important role in enabling new reactions.1m Typically this intermediate undergoes annulation with bis-nucleophiles, of which malonate-type enolates are most common. Recently bifunctional reagents (i.e., 2) have allowed more complicated cascades to be discovered, delivering various bicyclic-products (i.e., 3a).2,3 Strikingly the orthogonal approach, in which bifunctional α,β-unsaturated acyl azoliums (i.e., 4) are coupled with simple nucleophiles, are far less developed. Indeed, to the best of our knowledge, only a single report by Studer has demonstrated this strategy, in this case providing tricyclic δlactones (i.e., 5a) with excellent enantioselectivity via a Michael/Michael/δ-lactonization cascade.4 To expand NHCcatalysis with bifunctional acyl azolium catalysis we envisaged a synthesis of enantioenriched indenes (eq 1). While simple indenes are readily accessible,5 methods for the assembly of enantioenriched indenes are more limited, despite utility in medicinal chemistry (Scheme 1B).6 To date a handful of methods have been developed which exploit transition metal catalysis to give enantioenriched indenes,7 while fewer enantioselective organocatalytic approaches are known.8,9 To improve access to homochiral indenes we envisaged a bifunctional acyl azolium strategy (eq 1). Realization of this design would be the second example of a bifunctional acyl azolium reaction, and the first that exploits β-lactonization chemistry in the cyclization. Herein, we report studies on this topic, which have allowed the enantioselective NHC-catalyzed synthesis of 31 poly substituted indenes (i.e., 6). This represents one of the largest collections of enantioenriched indenes, with 30 being new materials. In addition, oxidative and reductive derivatizations are reported to further build molecular complexity. Use of acyl fluorides (i.e., 7) as acyl azolium precursors, although less common in acyl azolium catalysis than aldehydes, allows coupling with keto enolates rather than malonate-type nucleophiles used under oxidative conditions.10 Building on our knowledge of such substrates, and taking advantage of this © 2017 American Chemical Society
strength, studies commenced with TMS enol ether 8a and bifunctional acyl azolium precursor 7a. When exposed to a series of NHCs bearing N-substituents known to give more nucleophilic catalysts,11 the expected indene 6a formed with good levels of enantioinduction although poor yield (Table 1, entries 1−4). The unsuitability of weakly nucleophilic catalysts A5 (N-C6F5) and A6 (N-2,4,6-Cl3C6H2) was confirmed with Received: June 29, 2017 Published: August 16, 2017 4456
DOI: 10.1021/acs.orglett.7b01981 Org. Lett. 2017, 19, 4456−4459
Letter
Organic Letters Table 1. Optimization of the Synthesis of Indene 6a
Table 2. Scope of the Enantioselective Indene Synthesis
entry
NHC·BF4
base
solvent
% yielda
erb
1 2 3 4 5 6 7 8 9 10 11 12 13
A1 A2 A3 A4 A5/A6 B1 B2 B3 B1 ″ ″ ″ ″c
KHMDS ″ ″ ″ ″ ″ ″ ″ ″ ″ Cs2CO3 H+ sponge KHMDS
THF ″ ″ ″ ″ ″ ″ ″ DMF dioxane THF ″ ″
13 19 11 5 trace 42 20 13 50 15 trace 16 42
78:22 ″ 86:14 71:29 − 91:9 79:21 61:39 73:27 94:6 − 94:6 97:3
a Isolated yield following column chromatography. bEnantiomeric ratio by HPLC over chiral stationary phase. cCatalyst B1 isolated from potassium tetrafluoroborate byproduct (see Supporting Information).
both providing only a trace of indene 6a (Table 1, entry 5). Next, the three most successful N-substituents [Mes, t-Bu, and 2,6-(CH3O)2C6H3]12 were examined on the indanol scaffold (Table 1, entries 6−8). While all were viable, catalyst B1 was the most useful, improving enantioselectivity (to 91:9 er) and yield (to 42%) (Table 1, entry 6). Exploiting catalyst B1 with alternate bases for NHC generation and solvents was examined; however, such conditions failed to improve the yield or enantioselectivity of the reaction (Table 1, entries 9−12). In contrast, performing the reaction in the absence of salt byproducts13 improved the enantioselectivity to 97:3 er without changing the yield (Table 1, entry 13). Unfortunately, extensive modification of reaction conditions failed to increase the yield, which remained moderate due to competing dihydropyranone formation (6a′) and Claisen condensation (6a″).14 Nevertheless serviceable conditions had been identified, with the coupling of 8a and 7a defining one of the poorer outcomes of the study, with most transformations proceeding with better yield and >92:8 er (vide inf ra). Examination of the scope commenced by modifying the TMS enol ether partner 8. Alternate electron-rich and -poor acetophenone derived TMS enol ethers reacted smoothly to give indenes (6a−j) with yields between 42% and 66% and good levels of enantioselectivity (77:23 er to 99:1 er). Electronpoor substrates (Table 2, entries 5−10) generally gave higher yields, although at times at the expense of enantioselectivity. Heteroaryl TMS enol ethers were well suited to the reaction with 2-furyl containing indene 6k and 2-pyrdyl indene 6l formed in 58% and 60% yield and good enantioselectivity (92:8 er and 93:7 er respectively) (Table 2, entries 11 and 12). The
a
Isolated yield following column chromatography. bEnantiomeric ratio by HPLC over chiral stationary phase. c1 mmol scale.
TMS enol ether of acetone was also viable with indene 6m formed with high enantioselectivity (95:5 er); however, the yield was poor. Next, modification of the acyl azolium precursor 7 was examined with electron-rich R2 groups. When coupled to electron-rich, -neutral, or -poor TMS enol ethers, indenes 6n− 4457
DOI: 10.1021/acs.orglett.7b01981 Org. Lett. 2017, 19, 4456−4459
Letter
Organic Letters q formed in 91:9, 97:3, 89:11, and 71:29 er (Table 2, entries 14−17). The same electronic trends regarding yield and enantioselectivity were observed as discussed previously, while in general all reactions were slightly less selective than the variant bearing an electron-withdrawing R2 group. The selectivity of the reaction was decreased significantly with a 2,3-dimethoxyaryl R2 substituent giving indene 6r in 54:46 er (Table 2, entry 18). Indenes bearing a 5-methoxy group (i.e., 6s−w) were formed with comparable yield (48−66%) and enantioselectivity (83:17−97:3 er) compared to the unsubstituted variants (Table 2, entries 19−23). Similarly, indenes bearing a 6-Br (6x) or 6-CH3 group (6y) could be prepared, in this case with 95:5 and 98:2 er (Table 2, entries 24 and 25). The former was used to determine absolute stereochemistry through X-ray crystallographic studies.15 Next, introduction of aliphatic R2 substituents was examined. This had little impact on the yield or enantioselectivity of the reaction with indenes bearing a methyl (6z) or isopropyl group (6za−zc) formed in 91:9, 98:2, 94:6, and 88:12 er (Table 2, entries 26−29). The reaction tolerated trisubstituted TMS enol ethers giving indene 6zd with high enantioselectivity (97:3 er), although with moderate diastereoselectivity (3:1 dr) and yield (44%) (Table 2, entry 30). Finally, benzoannulation of the indene was possible with cyclopenta[a]naphthalene 6ze formed in 72% yield but with moderate enantioselectivity (60:40 er) (Table 2, entry 31). Simple derivatization of indene product 6c was examined (Scheme 2, eqs 4 and 5). Hydrogenation gave rise to 1,3disubstuted indane 9c without significant loss of enantiopurity (95:5 er from 99:1 er), >20:1 dr, and in 80% yield (eq 4). Using the same indene oxone based epoxidation afforded epoxide 10c in 72% yield, as a 2:1 mixture of diastereoisomers, with both isomers found to have greater than 97:3 er (eq 5). The use of ester enolates in acyl azolium catalysis is yet to be reported, with most work relying on malonate nucleophiles. Pleasingly ester enolates (i.e., derived from 11) gave the expected indene (eq 6); however, the enantioselectivitiy was low. We believe this implicates a background reaction that occurs with more nucleophilic substrates.16,17 Mechanistically the desired reaction commences with NHC defluorination/desilylation of the acyl fluoride 7 and TMS enol ether 8 to give acyl azolium 13 and enolate 14. With ketone enolates, 1,4-addition to the acyl azolium gives acyl azolium enolate 15. With ester enolates, the related, and nonenantioselective, addition to the acyl fluoride 7 can occur. In addition to such pathways the undesired Claisen condensation can occur to give 6″. Following the desired Michael addition to give 15 a pseudoconcerted (2 + 2) cycloaddition gives lactol 16,18 which, after expulsion of NHC B1 and decarboxylation, affords indene 6. Alternately proton transfer from acyl azolium enolate 15 and lactonization give dihydropyranone 6′. The chemistry of the α,β-unsaturated acyl azolium has proven highly useful for reaction discovery over the past decade. Herein, we report the second bifunctional acyl azolium based reaction design, and the first exploiting β-lactonization cyclization. Specifically the enantioselective synthesis of indenes has been developed, and a comprehensive survey of scope was performed (31 examples). The reaction is viable with various ketone enolates, although ester enolates react with low enantioselectivity. In general the yields are acceptable, although compromised by competing side reactions. Clearly a frontier that the NHC catalysis community must address to enhance the utility of these already highly valuable α,β-unsaturated acyl
Scheme 2. Derivatization, Ester Enolates, and Plausible Reaction Mechanism
azolium reactions is the discovery of acyl azolium analogs of greater electrophilicity. We are currently studying the electrophilcity of acyl azolium, and related structures, and will report a comprehensive survey of their properties in due course.17
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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.7b01981. Experimental procedures, 1H and 13C NMR of new materials and HPLC traces of chiral materials (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. 4458
DOI: 10.1021/acs.orglett.7b01981 Org. Lett. 2017, 19, 4456−4459
Letter
Organic Letters ORCID
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David W. Lupton: 0000-0002-0958-4298 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS D.W.L. thanks the ARC for financial support through the Future Fellowship and Discovery programs. REFERENCES
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