Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Remote Friedel−Crafts Reaction with α‑Heteroaryl-Substituted Cyclic Ketones via HOMO Activation of Lewis Bases Ben-Xian Xiao,† Chong-Hui Shi,† Shu-Yuan Liang,† Bo Jiang,† Wei Du,† and Ying-Chun Chen*,†,‡ †
Key Laboratory of Drug-Targeting and Drug Delivery System of the Ministry of Education and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China ‡ College of Pharmacy, Third Military Medical University, Shapingba, Chongqing 400038, China
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S Supporting Information *
ABSTRACT: Under the catalysis of Lewis bases, cyclic enones bearing an α-(2-furyl) motif can undergo remote Friedel− Crafts reaction with electrophilic reagents via a HOMO-activation strategy, proceeding in a formal vinylogous Rauhut−Currier or Morita−Baylis−Hillman-type reaction pattern. Moreover, even less reactive α-(2-benzofuranyl)-substituted cyclopeten-2ones can be similarly HOMO-raised and furnish [4 + 2] products with alkylidenemalononitriles in a cascade Friedel−Crafts/ Michael addition process.
T
Scheme 1. Lewis Base Catalysis and Vinylogous Activations
he Morita−Baylis−Hillman (MBH) or analogous Rauhut−Currier (RC) reaction provides an atom-economic and powerful protocol to construct multifunctional compounds.1 It is known that the established mechanism generally involves condensation between an activated alkene and a Lewis base (LB) catalyst, such as tertiary amine or phosphine, to generate HOMO-raised enolate-type species I, which can react with an electrophilic reagent to finally furnish the coupling of two electron-deficient substances. In the catalytic cycle, the reactive site is usually at the α-position, and the catalyst can be released after an α-proton transfer process (Scheme 1a).2 Although great progress has been made over the past decades, the reaction mode of MBH- or RC-type reactions of simple activated alkene substrates is generally monotonous under the catalysis of Lewis bases. Therefore, it is highly desirable to develop new reaction modes by rationally designing functionalized activated alkene precursors, which can be activated after the attack by Lewis bases.3 On the other hand, vinylogous activation can transfer the reactive position to a more remote site through conjugation with an unsaturated or π-system, offering the possibility of constructing products with fruitful functionalities.4 For example, our group disclosed that the furan ring could be HOMO-raised by forming conjugated enamine species II, thus effectively promoting the remote Friedel−Crafts (FC) alkylation reaction with a few electron-deficient reagents (Scheme 1b).5 We questioned whether the HOMO-raised nucleophilic species in situ generated in MBH- or RC-type activation could also be applicable to vinylogous reactions by connecting a suitable π-system, such as a 2-furyl group, to the α-site of an unsaturated carbonyl substrate, through generation of the conjugated zwitterionic intermediate III. It was envisioned that the α-site of enolate III would not be reactive © XXXX American Chemical Society
because of the lack of an α-H to regenerate the Lewis base catalyst. As a result, the furyl ring would be HOMO raised and participate in a remote FC alkylation reaction with suitable electrophiles accordingly, as outlined in Scheme 1c. Received: August 9, 2019
A
DOI: 10.1021/acs.orglett.9b02827 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Based on the above considerations, easily accessible α-(2furyl) cyclopenten-2-one6 1a was selected as the model substrate, which might be a particularly challenging substrate in RC- or MBH-type reactions due to the crowded trisubstituted pattern.7 It was pleasing that the coupling reaction of enone 1a and benzylidenemalononitrile 2a proceeded successfully under the catalysis of DMAP or DABCO in MeCN at 45 °C, and the remote FC product 3a was isolated in a moderate yield after 24 h (Table 1, entries 1
Table 2. Substrate Scope for FC Reaction of α-HeteroarylSubstituted Enones 1 and Alkylidenemalononitriles 2a
Table 1. Screening Conditions of FC Reaction of α-2Furylcyclopenten-2-one 1a and Benzylidenemalononitrile 2aa
entry
LB
solvent
T (°C)
t (h)
yieldb (%)
1 2 3 4 5 6 7 8 9e 10f 11e 12e 13e,g
DMAP DABCO PPh3 Cy3P nBu3P nBu3P nBu3P nBu3P nBu3P nBu3P nBu3P nBu3P nBu3P
MeCN MeCN MeCN MeCN MeCN toluene CHCl3 THF MeCN MeCN MeCN MeCN MeCN
45 45 45 45 45 45 45 45 45 45 60 70 60
24 24 24 48 24 36 12 36 24 24 12 12 20
56 46 NR 30 80 50 52 NR 85 73 90 90 78
entry
1
R
t (h)
yieldb (%)
1 2 3 4 5 6 7 8 9 10 11 12 13e 14 15 16 17 18 19e 20e,f
1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1b 1c 1d
Ph 2-FC6H4 2-ClC6H4 2-BrC6H4 3-ClC6H4 4-ClC6H4 4-BrC6H4 4-CF3C6H4 3-MeC6H4 4-MeC6H4 2-MeOC6H4 3-MeOC6H4 4-MeOC6H4 1-naphthyl 3-pyridyl 3-furyl Ph(CH2)2− Ph Ph Ph
12 12 12 12 12 12 12 12 12 24 24 12 24 12 12 36 36 12 36 36
3a, 90 3b, 75 3c, 80 3d, 81 3e, 78 3f, 87 3g, 85 (82)c,d 3h, 70 3i, 82 3j, 76 3k, 51 3l, 71 3m, 66 3n, 64 3o, 83 3p, 68 3q, 45 3r, 62 3s, 33 3t, 22
a Unless noted otherwise, reactions were performed with enone 1 (0.1 mmol), acceptor 2 (0.2 mmol), and nBu3P (20 mol %) in MeCN (0.5 mL) at 60 °C. bYield of the isolated product. cThe structure of racemic 3g was further determined by X-ray analysis. dData in parentheses were obtained on a 1.0 mmol scale. eWith nBu3P (40 mol %). fAt 80 °C.
a
Unless noted otherwise, reactions were performed with 2-furyl enone 1a (0.05 mmol), benzylidenemalononitrile 2a (0.1 mmol), and LB catalyst (20 mol %) in solvent (0.5 mL). bYield of the isolated product. eIn MeCN (0.25 mL). fIn MeCN (0.1 mL). gWith nBu3P (10 mol %).
15 and 16). In addition, the alkyl-substituted acceptor also underwent FC reaction with 1a, albeit in a fair yield (entry 17). On the other hand, different enone substrates 1 were explored. Cyclic enones 1b and 1c with a lager ring exhibited lower reactivity, and significantly reduced yields for products 3r and 3s were obtained (Table 2, entries 18 and 19). In addition, substrate 1d with a 2-thienyl motif could be similarly employed, but only a poor yield was produced even when catalyst loadings and reaction temperature were increased (entry 20). Apart from alkylidenemalononitriles 2, a variety of electrophiles were further explored. Although most of them showed low reactivity,8 the FC-type Mannich product 5 was efficiently furnished for the combination of cyclic N-sulfonylimine 4 and enone 1a, by using DMAP as the catalyst. In addition, an acyclic α-(2-furyl) cinnamaldehyde 6 also could be applied. While a mixture of Z- and E-isomers of the corresponding FC products was generated, the pure Z-product 7 could be smoothly isolated in a modest yield after reduction. On the other hand, acyclic α-(2-furyl)-benzylideneacetone 8 showed low reactivity in the FC-type Mannich reaction;8 however, it could react with acceptor 2a smoothly under the catalysis of nBu3P, affording product 9 in 52% yield as an inseparable mixture of Z/E isomers (Scheme 2). Meanwhile, we also attempted to extend this protocol to other aromatic systems.8 Notably, the less reactive α-(2-
and 2). Although PPh3 failed to promote the reaction (entry 3), more nucleophilic phosphine Cy3P was applicable (entry 4), and nBu3P showed high catalytic activity and gave a good yield (entry 5). A survey of the solvent effects revealed that MeCN was the optimal solvent (entries 6−8). Finally, it was found that a better yield could be obtained by slightly adjusting the concentration (entry 9 vs 10); meanwhile, the reaction time was significantly shortened with even better data at higher temperature (entries 11 and 12). Nevertheless, a reduced yield was observed with lower catalyst loadings (entry 13). Having established the optimal catalytic conditions, the substrate scope and limitations of the new FC reaction of αheteroaryl-substituted cyclic ketones and alkylidenemalononitriles were investigated. The results are summarized in Table 2. First, a number of acceptors 2 were investigated in combination with enone 1a. Acceptors 2 with a β-aryl ring bearing either an electron-withdrawing or electron-donating group were found to be well tolerated, giving the corresponding products 3b−n in moderate to high yields, though longer time or higher catalyst loadings were required in some cases (Table 2, entries 2−14). The reaction still proceeded efficiently on a 1.0 mmol scale, and a similar good yield was obtained (entry 2, data in parentheses). Heteroaryl-substituted electrophiles were compatible (entries B
DOI: 10.1021/acs.orglett.9b02827 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
1,1,1,3,3,3-hexafluoroisopropanol (HFIP) as the solvent could significantly facilitate the asymmetric reaction.7c,11 Because the reactive site of enone 1a or 10 is far away from the chiral phosphine catalyst C1, and HFIP might also affect the possible concerted hydrogen-bonding interaction of bifunctional phosphine C1; currently, only low to fair enantiocontrol could be achieved for both products 3a and 11a (Scheme 3),8 and further progress remains to be made.
Scheme 2. More FC-Type Reactions via Lewis Base Catalysis
Scheme 3. Attempts in Asymmetric Reactions via Chiral Lewis Base Catalysis
benzofuranyl) cyclopenten-2-one 10 could undergo FC alkylation reaction with acceptor 2a under the co-catalysis of nBu3P and salicylic acid (SA),9 and a cascade intramolecular Michael addition was followed to furnish a [4 + 2] annulation product 11a. It should be noted that the FC reaction of benzofurans has been rarely explored due to its low reactivity.10 The isolated yield of 11a was modest, whereas some byproducts were also detected as an inseparable mixture. As summarized in Table 3, an array of alkylidenemalononitriles
In conclusion, we have designed a new type of cyclic enone substrates bearing an α-2-furyl group. Such crowded trisubstituted activated alkenes still could be attacked by Lewis base catalysts to form conjugated zwitterionic enolate species and undergo remote Rauhut−Currier or Morita− Baylis−Hillman-type Friedel−Crafts reaction with suitable electrophiles via an unprecedented vinylogous HOMOactivation strategy. Even the less reactive benzofuran ring could be similarly activated, and a cascade Friedel−Crafts alkylation/Michael addition process was realized to deliver fused frameworks in a [4 + 2] annulation pattern. This work provides a new activation and reactive mode for classical Lewis base catalysis, which will find more applications in the construction of complex and multifunctional compounds upon rational design. More results will be reported in due course.
Table 3. Substrate Scope of [4 + 2] Annulations of Enone 10 and Alkylidenemalononitriles 2a
entry
R
t (h)
yieldb (%)
1 2 3 4 5 6 7 8 9 10
Ph 2-FC6H4 2-ClC6H4 4-ClC6H4 4-BrC6H4 4-CF3C6H4 4-MeC6H4 3-MeOC6H4 3-furyl Ph(CH2)2−
24 24 24 24 24 24 36 24 24 24
11a, 51c 11b, 71 11c, 63 11d, 63 11e, 57 11f, 51 11g, 63 11h, 55 11i, 56 11j, 71
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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.9b02827. Complete experimental procedures and characterization of the products; crystallographic data for racemic 3g and 11a; NMR spectra and HPLC chromatograms (PDF)
a
Unless noted otherwise, reactions were performed with enone 10 (0.1 mmol), acceptor 2 (0.2 mmol), nBu3P (30 mol %), and SA (30 mol %) in toluene (1.0 mL) at 40 °C. bYield of the isolated product; dr (>19:1) determined by 1H NMR analysis. cThe structure of racemic 11a was further determined by X-ray analysis.
Accession Codes
CCDC 1946276−1946277 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.
2 were tested in the reactions with enone 10, and the desired fused frameworks 11b−j were consistently obtained in comparable yields (entries 2−10). Finally, we also devoted great effort to explore the potential enantioselective remote FC reactions. Unfortunately, most common chiral Lewis base catalysts showed poor catalytic activity, probably due to the challenging trisubstituted pattern of the applied enone substrates. 7 Interestingly, using
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. C
DOI: 10.1021/acs.orglett.9b02827 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters ORCID
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Ying-Chun Chen: 0000-0003-1902-0979 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful for the financial support from the NSFC (21572135 and 21931006) and the Fundamental Research Funds for the Central Universities.
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DOI: 10.1021/acs.orglett.9b02827 Org. Lett. XXXX, XXX, XXX−XXX
