Abstract
A (pybox)Ni catalyst (pybox = pyridine–bis(oxazoline)) promotes the reductive cyclization of β-hydroxy 1,1-dichloroalkenes to form 2,3-dihydrofurans. The substrates for this reaction are conveniently prepared by an aldol addition followed by one-carbon homologation. Chiral substrates are accessible in highly enantioenriched form, allowing for the synthesis of stereochemically complex 2,3,4-trisubstituted products. Mechanistic studies support a vinylidene O–H insertion pathway rather than C–O cross-coupling followed by reductive dechlorination.
Keywords: vinylidenes, O–H bond insertion, cyclization, oxygen heterocycles, nickel catalysis
Graphical Abstract
Oxolanes and their unsaturated derivatives are found in numerous polyoxygenated natural products.1 Additionally, they have been incorporated into synthetic biologically active compounds as conformationally constrained hydrogen-bond acceptors.2 Oxolanes can be synthesized using intramolecular C–O bond-forming reactions.3 One way to accomplish this bond construction is through the insertion of a divalent carbon atom into an O–H bond. There are many examples of catalytic carbene insertions into O–H bonds using diazoalkanes.4 However, insertions of vinylidenes into O–H bonds are more limited in scope,5 despite their potential value in the preparation of unsaturated oxolanes such as 2,3-dihydrofurans and furans.
The principle challenge in developing such a reaction is that methods to access free vinylidenes typically require the use of a strong base, such as KHMDS or MeLi, which is incompatible with free alcohols (Figure 1).6 In an alternative approach, transition metal vinylidene complexes can be generated from the isomerization of an alkyne.7 However, this rearrangement can only be carried out with terminal alkynes, because alkyl and aryl groups do not undergo 1,2-shifts as readily as H atoms.
Figure 1.
Challenges associated with designing O–H insertion reactions of free vinylidenes or metal-bound vinylidenes. A nickel-catalyzed reductive cyclization of β-hydroxy 1,1-dichloroalkenes.
Recently, we showed that transition metal catalysts can react with 1,1-dichloroalkenes to generate metal vinylidene species that participate in cycloaddition reactions.8 Catalytic turnover is achieved using reductants such as Zn or Mn, which are sufficiently mild to be compatible with free alcohols. We reasoned that this approach to vinylidene generation may enable the development of insertion reactions into relatively acidic E–H bonds. Additionally, by not relying on alkyne isomerization to generate the vinylidene fragment, it should be possible to access products substituted at the 4-position. Here, we report a nickel catalyzed reductive 1,5 O–H insertion reaction of vinylidenes. The substrates for this cyclization are conveniently synthesized using aldol reactions, providing a straightforward route to polysubstituted 2,3-dihydrofurans with control over absolute and relative stereochemistry.
Following our reaction development studies, we arrived at an optimized set of conditions for the reductive cyclization of β-hydroxy 1,1-dichloroalkene 1 (Table 1). 2,3-Dihydrofuran 2 was obtained in 89% yield using a (i-Prpybox)NiCl2 catalyst (10 mol%) (entry 1). Control experiments indicated that both the Ni source and the PyBox ligand were required for the reaction to proceed (entries 2 and 3). Other tridentate and bidentate nitrogen-donor ligands were also tested but found to give inferior yields (entries 5, 6, and Supporting Information). Zn provided the highest yields of product. However, some amount of 2 could still be obtained with Mn or Cp2Co (entries 7 and 8). The solvent proved to be an important reaction parameter, with a mixture of CH3CN and NMP (4:1) being optimal. Using other solvents (entry 9), the reaction mixture contained a side product in which the alkene had isomerized into conjugation with the naphthyl group.
Table 1.
Effect of Reaction Parameters in the Reductive Cyclization.
 | ||
|---|---|---|
| entry | variation from standard conditionsa | yield 2 |
| 1 | none | 89% |
| 2 | No Ni(dme)Cl2 | 0% |
| 3 | No (±)-i-PrPyBox (3) | 0% |
| 4 | Co(dme)Cl2 instead of Ni(dme)Cl2 | 2% |
| 5 | (±)t-BuPyBox (4) instead of 3 | 36% |
| 6 | DIPPPDI (5) instead of 3 | 11% |
| 7 | Mn instead of Zn | 59% |
| 8 | Cp2Co instead of Zn | 18% |
| 9 | CH3CN only | 16% |
Standard reaction conditions:substrate 1 (0.11 mmol, 1.0 equiv), Zn (3.0equiv), Ni(dme)Cl2 (0.10 equiv), (±)-i-PrPyBox (0.10 equiv), 4:1 NMP/CH3CN, 24 h, rt. Yields of 2 were determined by GC analysis using p-xylene as an internal standard.
The substrate scope for the vinylidene 1,5 O–H insertion reaction is summarized in Figure 2. 2,3-Dihydrofuran products bearing various combinations of substituents at the 2-, 3-, and 4-position were obtained in high yield. Branched alkyl, linear alkyl, heteroaryl, and aryl substitutents are tolerated on the 1,1-dichloroalkene. Common functional groups, including aryl chlorides (product 14) and aryl boronate esters (product 18), which are used in cross-coupling reactions, are compatible with the reaction conditions. Electron-rich heterocycles (products 8, 9, and 20) could be present in the substrate. Lewis basic heterocycles, such as quinolines (product 10), often inhibit transition metal catalysts but were found to be tolerated. Finally, substrates derived from cyclic ketones underwent cyclization to form fused bicyclic dihydrofurans (products 23–25).
Figure 2.
Substrate scope studies. Standard reaction conditions: substrate (0.05–0.26 mmol scale, 1.0 equiv), Zn (3.0 equiv), Ni(dme)Cl2 (0.10 equiv), (±)-i-PrPyBox (0.10 equiv), 4:1 NMP/CH3CN, 24 h, rt. Yields are of isolated products following purification by column chromatography. a Using 20 mol% catalyst loading.
We next explored the enantio- and diastereoselective synthesis of 2,3-disubstituted dihydrofurans by employing asymmetric aldol reactions to prepare the requisite β-hydroxy 1,1-dichloroalkene substrates (Figure 3A). Substrate 26 was synthesized using an Evans auxiliary syn-aldol reaction.9 The reductive cyclization generated dihydrofuran 27 in 56% yield (>99% ee, >20:1 dr). The corresponding anti-diastereomer was also accessible via a Paterson anti-aldol reaction.10 Product 29 was obtained in 72% yield (96% ee, >20:1 dr).
Figure 3.
Synthetic applications of the reductive 1,5 O–H insertion reaction. (a) Synthesis of 2,3,4-trisubstituted 2,3-dihydrofurans in highly enantio- and diastereoenriched forms. (b) Synthesis of furans by tandem vinylidene O–H insertion and alkene isomerization. (c) Preparing a natural product derivative containing a fused 2,3-dihydrofuran. Steps involved in the preparation of substrates 26, 28, 30, and 32 are detailed in the Supporting Information.
Furan products could be prepared by carrying out a tandem vinylidene O–H insertion followed by alkene isomerization (Figure 3B). The 1,1-dichlorodiene 30 was prepared using a Morita–Baylis–Hillman reaction.11 Subjecting 30 to the standard reductive cyclization conditions provided bicyclic furan 31. The yield of the furan was maximized by employing an acidic workup following the cyclization.12
Finally, the vinylidene O–H insertion reaction was applied to the derivatization of a natural product (Figure 3C). (+)-4-Cholesten-3-one possesses an enone on the A ring, and aldol addition of 4-fluorobenzaldehyde followed by one-carbon homologation yielded 32. Cyclization proceeded smoothly under the standard catalytic conditions to provide the conjugated 2,3-dihydrofuran product 33 in 78% yield.
Mechanistic possibilities for the reductive cyclization reaction are shown in Figure 4. Reduction of the (i-Prpybox)NiCl2 precatalyst (34) using Zn generates (i-Prpybox)NiCl (35), which can engage the 1,1-dichloroalkene in a C–Cl oxidative addition reaction.13 From the resulting 1-chloroalkenyl intermediate 36, there are two major pathways to consider. In the first, oxidative addition of the second C–Cl bond triggered by Zn reduction would generate a nickel vinylidene (37). Cyclization could then occur by a concerted O–H insertion or a stepwise process, such as nucleophilic attack of the alcohol on the nickel vinylidene followed by protonolysis.7e,7f In the second pathway, the 1-chloroalkenyl intermediate could undergo C–O cross-coupling by deprotonation to form nickel alkoxide 38 followed by C–O reductive elimination.14 In order to generate the final product of the reaction, the 5-chloro-2,3-dihydrofuran would then need to be reductively dehalogenated or transformed into an organozinc species that is protonated during workup.
Figure 4.
Vinylidene O–H insertion (top) vs. C–O cross-coupling mechanisms (bottom).
There are several pieces of evidence that support a vinylidene pathway over a C–O cross-coupling pathway. The deuterium-labelled substrate 39-d1 was prepared by dissolving all-protio 39 in MeOD and evaporating the solvent under vacuum. Subjecting 39-d1 to the standard reductive cyclization conditions yielded the cyclized product 6-d1 with 85% deuterium incorporation at the 5-position (Figure 5A). In a complementary experiment, a catalytic cyclization reaction of the all-protio substrate 39 was quenched with D2O (Figure 5B). There was no deuterium incorporation in product 6 in this case. These two experiments confirm that the hydroxyl group in the substrate is the source of the H-atom at C5 and that the reaction does not produce an 2,3-dihydrofuryl zinc compound that is quenched during workup.
Figure 5.
Experiments distinguishing between vinylidene O–H insertion and C–O cross-coupling mechanisms.
Next, the 5-chloro-2,3-dihydrofuran 40 was prepared15 and subjected to the standard catalytic conditions (Figure 5C). There is a trace amount of the dehalogenated product that is formed (5% yield). However, the yield is not commensurate with that of the catalytic cyclization reaction. Therefore, 40 can be ruled out as an intermediate. We also note that the monochloroalkene substrate 41 does not undergo cyclization under the standard catalytic conditions and is recovered after 24 h at room temperature in (91% recovery of 41) (Figure 5D). This result suggests that the reaction does not involve an initial reductive dechlorination followed by intramolecular C–O cross-coupling.
Finally, we examined whether the only role of Zn in the reaction is to reduce the Ni catalyst or whether it may be more intimately involved the mechanism of cyclization—for example, by generating organozinc intermediates.16 To test this possibility, the (i-Prpybox)NiBr complex (42) was synthesized according to procedures reported by Fu.13b Reacting 42 (1.0 equiv) with 1 (5.0 equiv) yielded the (i-Prpybox)NiX2 complex 43 and the cyclization product 2 (Figure 6). The amount of 2 produced corresponds to a yield of 80% assuming that two equivalents of 42 are required for each equivalent of 2 that is generated. Thus, the presence of Zn is not required for the cyclization to occur.
Figure 6.
Stoichiometric reductive cyclization using a reduced nickel complex in the absence of Zn.
In summary, a nickel catalyst can be used to generate reactive vinylidene species from 1,1-dichloroalkenes under mildly reducing and non-basic conditions. This process enabled the development of high-yielding intramolecular insertions of vinylidenes into O–H bonds. The net reductive cyclization provides access to polysubstituted 2,3-dihydrofurans. Ongoing studies are aimed at generalizing this approach to other bond insertion processes.
Supplementary Material
ACKNOWLEDGMENT
We thank Prof. Nathan Schley for helpful discussions. This research was supported by the NIH (R35 GM124791). C.U. acknowledges support from a Camille Dreyfus Teacher–Scholar award and a Lilly Grantee award.
Footnotes
The authors declare no competing financial interest
ASSOCIATED CONTENT
The Supporting Information is available free of charge at http://pubs.acs.org
Experimental procedures and characterization data (PDF)
REFERENCES
- (1).(a) Kang EJ; Lee E “Total synthesis of oxacyclic macrodiolide natural products” Chem. Rev 2005, 105, 4348–4378; [DOI] [PubMed] [Google Scholar]; (b) Lorente A; Lamariano-Merketegi J; Albericio F; Álvarez M “Tetrahydrofuran-containing macrolides: A fascinating gift from the deep sea” Chem. Rev 2013, 113, 4567–4610; [DOI] [PubMed] [Google Scholar]; (c) de la Torre A; Cuyamendous C; Bultel-Poncé V; Durand T; Galano J-M; Oger C “Recent advances in the synthesis of tetrahydrofurans and applications in total synthesis” Tetrahedron 2016, 72, 5003–5025. [Google Scholar]
- (2).(a) Babine RE; Bender SL “Molecular recognition of protein−ligand complexes: Applications to drug design” Chem. Rev 1997, 97, 1359–1472; [DOI] [PubMed] [Google Scholar]; (b) Ghosh AK; Ramu Sridhar P; Kumaragurubaran N; Koh Y; Weber IT; Mitsuya H “Bis-tetrahydrofuran: A privileged ligand for darunavir and a new generation of hiv protease inhibitors that combat drug resistance” ChemMedChem 2006, 1, 939–950; [DOI] [PubMed] [Google Scholar]; (c) Delost MD; Smith DT; Anderson BJ; Njardarson JT “From oxiranes to oligomers: Architectures of U.S. FDA approved pharmaceuticals containing oxygen heterocycles” J. Med. Chem 2018, 61, 10996–11020. [DOI] [PubMed] [Google Scholar]
- (3).(a) Alonso F; Beletskaya IP; Yus M “Transition-metal-catalyzed addition of heteroatom−hydrogen bonds to alkynes” Chem. Rev 2004, 104, 3079–3160; [DOI] [PubMed] [Google Scholar]; (b) Nakamura I; Yamamoto Y “Transition-metal-catalyzed reactions in heterocyclic synthesis” Chem. Rev 2004, 104, 2127–2198; [DOI] [PubMed] [Google Scholar]; (c) Hashmi ASK “Gold-catalyzed organic reactions” Chem. Rev 2007, 107, 3180–3211; [DOI] [PubMed] [Google Scholar]; (d) Gulevich AV; Dudnik AS; Chernyak N; Gevorgyan V “Transition metal-mediated synthesis of monocyclic aromatic heterocycles” Chem. Rev 2013, 113, 3084–3213; [DOI] [PMC free article] [PubMed] [Google Scholar]; (e) Chinchilla R; Nájera C “Chemicals from alkynes with palladium catalysts” Chem. Rev 2014, 114, 1783–1826. [DOI] [PubMed] [Google Scholar]
- (4).(a) Miller DJ; Moody CJ “Synthetic applications of the O-H insertion reactions of carbenes and carbenoids derived from diazocarbonyl and related diazo-compounds” Tetrahedron 1995, 51, 10811–10843; [Google Scholar]; (b) Zhang ZH; Wang JB “Recent studies on the reactions of alpha-diazocarbonyl compounds” Tetrahedron 2008, 64, 6577–6605; [Google Scholar]; (c) Gillingham D; Fei N “Catalytic X–H insertion reactions based on carbenoids” Chem. Soc. Rev 2013, 42, 4918–4931; [DOI] [PubMed] [Google Scholar]; (d) Ford A; Miel H; Ring A; Slattery CN; Maguire AR; McKervey MA “Modern organic synthesis with α-diazocarbonyl compounds” Chem. Rev 2015, 115, 9981–10080. [DOI] [PubMed] [Google Scholar]
- (5).(a) Baird MS; Baxter AGW; Hoorfar A; Jefferies I “Ring-size and substituent effects in intramolecular reactions of alkylidenecarbenes (carbenoids)” J. Chem. Soc., Perkin Trans 1 1991, 2575–2581; [Google Scholar]; (b) Yanagisawa H; Miura K; Kitamura M; Narasaka K; Ando K “Intramolecular substitution reaction of alkylidene-lithium carbenoids: Regioselective synthesis of indenes” Helv. Chim. Acta 2002, 85, 3130–3135; [Google Scholar]; (c) Hideyuki Y; Kasei M; Mitsuru K; Koichi N; Kaori A “Intramolecular substitution reaction of lithium alkylidene carbenoids. Regioselective synthesis of indenes” Bull. Chem. Soc. Jpn 2003, 76, 2009–2026. [Google Scholar]
- (6).Knorr R “Alkylidenecarbenes, alkylidenecarbenoids, and competing species: Which is responsible for vinylic nucleophilic substitution, [1 + 2] cycloadditions, 1,5-CH insertions, and the Fritsch-Buttenberg-Wiechell rearrangement?” Chem. Rev 2004, 104, 3795–3850. [DOI] [PubMed] [Google Scholar]
- (7).(a) Mcdonald FE; Connolly CB; Gleason MM; Towne TB; Treiber KD “A new synthesis of 2,3-dihydrofurans - cycloisomerization of alkynyl alcohols to endocyclic enol ethers” J Org Chem 1993, 58, 6952–6953; [Google Scholar]; (b) McDonald FE; Gleason MM “Asymmetric syntheses of stavudine (d4t) and cordycepin by cycloisomerization of alkynyl alcohols to endocyclic enol ethers” Angew. Chem., Int. Ed 1995, 34, 350–352; [Google Scholar]; (c) Schmidt B; Kocienski P; Reid G “A synthesis of oxolenes and furans via oxacyclopentylidene chromium and molybdenum complexes” Tetrahedron 1996, 52, 1617–1630; [Google Scholar]; (d) Trost BM; Rhee YH “A Rh(I)-catalyzed cycloisomerization of homo- and bis-homopropargylic alcohols” J. Am. Chem. Soc 2003, 125, 7482–7483; [DOI] [PubMed] [Google Scholar]; (e) Bruneau C; Dixneuf PH “Metal vinylidenes and allenylidenes in catalysis: Applications in anti-Markovnikov additions to terminal alkynes and alkene metathesis” Angew. Chem., Int. Ed 2006, 45, 2176–2203; [DOI] [PubMed] [Google Scholar]; (f) Bruneau C; Dixneuf P Metal vinylidenes and allenylidenes in catalysis: From reactivity to applications in synthesis; John Wiley & Sons, 2008; [Google Scholar]; (g) Roh SW; Choi K; Lee C “Transition metal vinylidene- and allenylidene-mediated catalysis in organic synthesis” Chem. Rev 2019, 119, 4293–4356. [DOI] [PubMed] [Google Scholar]
- (8).(a) Zhou YY; Uyeda C “Catalytic reductive [4 + 1]-cycloadditions of vinylidenes and dienes” Science 2019, 363, 857–862; [DOI] [PMC free article] [PubMed] [Google Scholar]; (b) Farley CM; Sasakura K; Zhou YY; Kanale VV; Uyeda C “Catalytic [5 + 1]-cycloadditions of vinylcyclopropanes and vinylidenes” J. Am. Chem. Soc 2020, 142, 4598–4603. [DOI] [PMC free article] [PubMed] [Google Scholar]
- (9).Evans DA; Bartroli J; Shih TL “Enantioselective aldol condensations. 2. Erythro-selective chiral aldol condensations via boron enolates” J. Am. Chem. Soc 1981, 103, 2127–2129. [Google Scholar]
- (10).Paterson I; Wallace DJ; Cowden CJ “Polyketide synthesis using the boron-mediated, anti-aldol reactions of lactate-derived ketones: Total synthesis of (−)-ACRL, toxin IIIb” Synthesis 1998, 639–652. [Google Scholar]
- (11).Bugarin A; Connell BT “Acceleration of the Morita-Baylis-Hillman reaction by a simple mixed catalyst system” J. Org. Chem 2009, 74, 4638–4641. [DOI] [PubMed] [Google Scholar]
- (12).Tsuji J; Watanabe H; Minami I; Shimizu I “Novel palladium-catalyzed reactions of propargyl carbonates with carbonucleophiles under neutral conditions” J. Am. Chem. Soc 1985, 107, 2196–2198. [Google Scholar]
- (13).(a) Jones GD; Martin JL; McFarland C; Allen OR; Hall RE; Haley AD; Brandon RJ; Konovalova T; Desrochers PJ; Pulay P; Vicic DA “Ligand redox effects in the synthesis, electronic structure, and reactivity of an alkyl−alkyl cross-coupling catalyst” J. Am. Chem. Soc 2006, 128, 13175–13183; [DOI] [PubMed] [Google Scholar]; (b) Schley ND; Fu GC “Nickel-catalyzed Negishi arylations of propargylic bromides: A mechanistic investigation” J. Am. Chem. Soc 2014, 136, 16588–16593. [DOI] [PMC free article] [PubMed] [Google Scholar]
- (14).(a) Thielges S; Meddah E; Bisseret P; Eustache J “New synthesis of benzo[b]furan and indole derivatives from 1,1-dibromo-1-alkenes using a tandem Pd-assisted cyclization–coupling reaction” Tetrahedron Lett. 2004, 45, 907–910; [Google Scholar]; (b) Nagamochi M; Fang Y-Q; Lautens M “A general and practical method of alkynyl indole and benzofuran synthesis via tandem Cu- and Pd-catalyzed cross-couplings” Org. Lett 2007, 9, 2955–2958; [DOI] [PubMed] [Google Scholar]; (c) Newman SG; Aureggi V; Bryan CS; Lautens M “Intramolecular cross-coupling of gem-dibromoolefins: A mild approach to 2-bromo benzofused heterocycles” Chem. Commun 2009, 5236–5238; [DOI] [PubMed] [Google Scholar]; (d) Chelucci G “Synthesis and metal-catalyzed reactions of gem-dihalovinyl systems” Chem. Rev 2012, 112, 1344–1462. [DOI] [PubMed] [Google Scholar]
- (15).Ye SQ; Liu G; Pu SZ; Wu J “Synthesis of 2-(polyfluoroaryl)benzofurans via a copper(I)-catalyzed reaction of 2-(2,2-dibromovinyl)phenol with polyfluoroarene” Org. Lett 2012, 14, 70–73. [DOI] [PubMed] [Google Scholar]
- (16).(a) Olivares AM; Weix DJ “Multimetallic Ni- and Pd-catalyzed cross-electrophile coupling to form highly substituted 1,3-dienes” J. Am. Chem. Soc 2018, 140, 2446–2449; [DOI] [PMC free article] [PubMed] [Google Scholar]; (b) Kang K; Huang L; Weix DJ “Sulfonate versus sulfonate: nickel and palladium multimetallic cross-electrophile coupling of aryl triflates with aryl tosylates” J. Am. Chem. Soc 2020, 142, 10634–10640. [DOI] [PMC free article] [PubMed] [Google Scholar]
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