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Efficient Formation of 2,3-Dihydrofurans via IronCatalyzed Cycloisomerization of #-Allenols Arnar Guðmundsson, Karl Gustafson, Binh Khanh Mai, Bin Yang, Fahmi Himo, and Jan-E. Bäckvall ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b03515 • Publication Date (Web): 20 Nov 2017 Downloaded from http://pubs.acs.org on November 20, 2017
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Efficient Formation of 2,3-Dihydrofurans Cycloisomerization of α-Allenols
via
Iron-Catalyzed
Arnar Guðmundsson, Karl P. J. Gustafson, Binh Khanh Mai, Bin Yang*, Fahmi Himo*, and Jan-E. Bäckvall* Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden Supporting Information ABSTRACT: Herein, we report a highly efficient iron-catalyzed intramolecular nucleophilic cyclization of α-allenols to furnish substituted 2,3-dihydrofurans under mild reaction conditions. A highly diastereoselective variant of the reaction was developed as well, giving diastereomeric ratios of up to 98:2. The combination of the iron-catalyzed cycloisomerization with enzymatic resolution afforded the 2,3-dihydrofuran in high ee. A detailed DFT study provides insight into the reaction mechanism and gives a rationalization for the high chemo- and diastereoselectivity. KEYWORDS: Iron catalysis, 2,3-dihydrofurans, homogeneous.
-allenols, diastereoselective,
As the most abundant transition metal, iron, with its low price and toxicity, has been studied intensively for catalytic reactions.1 The role of iron in catalysis is multifaceted. It can catalyze cross-couplings2 and redox reactions such as transfer hydrogenation,3 as well as reactions via carbene or nitrene intermediates.4 Recently, there has been great interest in the development of iron-based transfer hydrogenation catalysts.3,5 Catalyst 2 (Scheme 1) was originally isolated by the group of Knölker in 1999,6,7 although, its first catalytic application was not demonstrated until 2007 when Casey and Guan reported its use in the hydrogenation of ketones and aldehydes to alcohols.5 Iron complexes 2 and A are isoelectronic analogues to ruthenium complexes 4 and B, respectively, obtained from Shvo’s catalyst 3.8 Complexes A and 2 can be generated in situ from air- and moisture stable precursor 1. This has allowed for numerous applications in various transfer hydrogenation reactions including the alkylation of amines or carbonyls using alcohols.9 Scheme 1. Iron- and Hydrogenation Catalysts
Ruthenium-Based
An iron-based racemization protocol for secondary alcohols, an important extension of transfer hydrogenation catalysis, was recently developed in our group using a pincer type iron catalyst.10 Unfortunately, this catalyst was not compatible with the reaction conditions required for chemoenzymatic dynamic kinetic resolution (DKR). Subsequently, 1 and 2 were employed as racemization catalysts in chemoenzymatic DKR of secondary alcohols by Rueping’s and our group.11 Although transition metal-catalyzed cyclizations of allenes have been studied extensively,12 the development of novel cyclization methods for substituted allenes through iron catalysis is still lacking. We recently reported13 a one-pot lipase/Ru-catalyzed kinetic resolution of -allenols followed by cycloisomerization using catalyst 3, via intermediate B (Scheme 2a). This reaction furnished enantiomerically pure 2,3-dihydrofurans, the formation of which was postulated to proceed via a Ru-carbene intermediate.13 From that work (Scheme 2a) and our experience with iron catalyst 111b we envisioned that species A, generated from 1, might catalyze a similar cyclization of -allenols to furnish substituted 2,3-dihydrofurans (Scheme 2b). In contrast to catalyst 3, which requires thermal activation to give B, generation of the 16-electron complex A from 1 occurs at room temperature, which could facilitate diastereoselective cyclization of 1,2-subsituted -allenols 5. Scheme 2. Previous Work and Proposal for This Work
Transfer
Initial attempts began by using anisole as solvent with 10 mol% of complex 1 as the catalyst and trimethylamine N-oxide (TMANO) as activator under Ar atmosphere at room temperature. This was the solvent of choice in our earlier related DKR study.11 Gratifyingly, the anticipated product 6a was obtained in 70%
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yield as the sole product (Table 1, entry 1). The iron-catalyzed protocol proceeded with exclusive chemoselectivity and the isomeric byproduct 2,5-dihydrofuran was not observed. Following these results, we turned to screening the reaction conditions with respect to catalyst loading and solvent. The reaction still proceeded well with a catalyst loading as low as 5 mol% (Table 1, entries 2 and 3). Solvent screening showed that non-polar solvents such as dichloromethane (DCM), ether and toluene (Table 1, entries 4-7) were superior to polar ones. Acetonitrile and water failed to give product 6a after 2 h, most likely due to the strong coordination by these solvents to iron and subsequent poisoning of the catalyst (Table 1, entries 8-12). DCM, owing to its low boiling point, was selected as the solvent of choice because of the relatively high volatility of 6a. Attempts to use a simple iron salt, Fe(OAc)2, were unsuccessful and did not yield any 6a. Table 1. Optimization of the Reaction Conditions
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α-allenols, we next turned our attention to the possible diastereoselectivity of the reaction. If a 1,2-disubstituted α-allenol is used, two diastereomeric forms of the 2,3-dihydrofuran are possible. The inherent mild reaction conditions of the iron-catalyzed cycloisomerization would increase the chances of obtaining high diastereoselectivity. We were pleased to find that these substituted α-allenols could be converted into the corresponding 2,3-dihydrofurans 6k-n in excellent yield and with a diastereomeric ratio (d.r.) of up to 98:2. It is worth noting that the d.r. of the previous Ru-protocol for the cyclization of the 1,2-disubstituted allenol to give product 6k is only 4:1, which further highlights the advantage of the iron-catalyzed cycloisomerization of -allenols. It is interesting to note that α-allenols, with an aryl substitution in the 2-position (5o), failed to yield any product (6o) under the standard reaction conditions, which most likely can be attributed to the increased stability of the allene. Scheme 3. Substrate Scope for the Iron-catalyzed Cycloisomerization of -Allenols 5 to form 2,3-Dihydrofuran 6
Entry
Solvent
Yield after 2 hb (%)
Anisole
Catalyst loading (mol%) 10
1 2
Anisole
5
50 %
3
Anisole
2.5
14 %
4
DCM
5
90 %
5
Diethyl Ether
5
82 %
6
Toluene
5
95 %
7
CPMEc
5
24 %
8
EtOAc
5
18 %
9
THF
5
11 %
10
Acetonitrile
5
0%
11
DMF
5
3%
12
Water
5
0%
70 %
a
General reaction conditions: The reaction was conducted under Ar atmosphere at r.t. with 0.5 mmol of 5a, 0.05 mmol of 1, 0.1 mmol of TMANO, 0.5 mmol of K2CO3 and 0.5 mL of solvent. bYield determined by 1H NMR analysis. c Cyclopentyl methyl ether. With the optimal conditions in hand (5 mol% of 1 in DCM), we next studied the reactivity of various functionalized allenols (Scheme 3). Derivatives bearing electron-donating (5b, 5c), electron-neutral (5a and 5d), or electron-withdrawing substituents (5e, 5f) on the aryl group all gave good to excellent yields. Substituents on the aryl ring in the meta or ortho position had little effect on the reaction and furnished the 2,3-dihydrofurans 6g and 6h in good yields. When an aliphatic substituent was present instead of the aryl group, the reaction proceeded equally well, giving 92% isolated yield of 6i. Dihydrofuran 6j with a heterocyclic group in the 2-position could be obtained as well, in 94% yield. After exploring the reactivity of 1-substituted
We next investigated the effect of substitution at the terminal allenic position. Subjecting 5p to the standard reaction conditions afforded only 26% of product. However, when the reaction was conducted in toluene at 70 °C, the 2,5-disubstituted 2,3-dihydrofuran 6p was obtained in 96% yield (eq. 1). While monitoring the reaction, it was observed that at 65% conversion the remaining starting material had a diastereomeric ratio of approximately 8:1, showing that the diastereoisomers of 5p react with substantially different rates.
We also investigated the cycloisomerization in combination with enzymatic resolution (eq. 2). Kinetic resolution of 5a with Candida antarctica lipase B (CalB) afforded (S)-5a (97% ee), which was used for cycloisomerization. In view of the fact that
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iron complex 1 works as racemization catalyst in DKR of sec-alcohols,11b complex 1 may cause racemization of starting material (S)-5a. To our delight, the reaction proceeded without any loss of chirality, yielding (S)-6a in 80% yield and 97% ee. This is in accordance with the results from the corresponding Ru-catalyzed reaction.13
Control experiments using 2,5-dihydrofuran as the starting material were performed (eq. 3). When 7 was exposed to the standard reaction conditions, no reaction occurred, suggesting that 7 is not an intermediate species in the reaction.
To gain a deeper insight into the mechanism of this novel cycloisomerization by iron, we performed density functional theory (DFT) calculations using the formation of 6k as a model (see SI for computational details). On the basis of these calculations we propose the reaction mechanism shown in Scheme 4. The catalytic cycle starts with coordination of the substrate to A, which is obtained from activation of iron complex 1. Interestingly, the lowest-energy binding mode was found to be coordination by the hydroxyl group to give Int-0, which is similar in structure to what Casey and Guan observed.5b The productive coordination by the terminal C=C bond of the allene moiety giving Int-1 is calculated to be 8.1 kcal/mol higher in energy. From Int-1, cyclization via TS-1 can then take place to produce vinyl iron intermediate Int-2 (see Figure 1). The calculations show that the lowest-energy TS for this step involves another allenol molecule that assists in shuttling the proton (see Figure 1). The barrier for this step is calculated to be 19.2 kcal/mol relative to Int-0. Next, isomerization of Int-2 to Int-4 is shown to proceed via the key iron carbene intermediate Int-3. This isomerization consists of two proton transfer steps in which the non-innocent cyclopentadienone ligand plays an important role. Subsequent protodemetalation of Int-4 gives Int-5, which on release of product 6 regenerates A, thereby closing the catalytic cycle. According to the calculations, TS-2 is the rate determining step (RDS) of the reaction, with an overall barrier of 20.9 kcal/mol (see Figure 1). However, the other steps are quite close in energy (19.2, 20.0, and 18.8 kcal/mol, for TS-1, TS-3, and TS-4, respectively), and it is therefore not possible to confidently assign the RDS on the basis of the calculations alone. In the reaction of 5k, only 6k was observed as product. We have also considered the formation of the cis isomer of 6k, which requires the protonation at TS-2 to take place from the other face of the double bond. For this to happen, a rotation around the Fe-C bond has first to occur to give Int-2’ (Figure 1). The barrier for the subsequent transition state, TS-2’, is calculated to be 1.8 kcal/mol higher than TS-2 , which corresponds to a d.r. of about 95:5, in good agreement with the experimental findings (Scheme 3).14
protodemetalation already at Int-2 leading to 2,5-dihydrofuran. The TS for this step, called TS-PD in Figure 1, is calculated to be 5.7 kcal/mol higher in energy than TS-2 that gives the correct product. This result is consistent with the experimental observations that 2,3-dihydrofurans 6 are exclusively formed and that 2,5-dihydrofurans are not intermediates (eq. 3). TS-2 has a more relaxed 6-membered TS structure, compared to the more strained 5-membered TS of TS-PD, which in addition lacks the stabilizing CH-O interaction present in TS-2 (see SI).
Scheme 4. Reaction Mechanism for the Iron-Catalyzed Cycloisomerization Proposed on the Basis of Current DFT Calculations
Finally, it was found that the proposed mechanism is consistent with deuterium-labeling experiments (see Supporting Information S1 and S2). In all of the labeling experiments there was no loss of deuterium in the 5-position of the 2,3-dihydrofuran when 4,4-dideuterated α-allenol was used. This observation suggests that the step from Int-3 to Int-4 is irreversible. We also observed a small kinetic isotope effect (KIE) of kH/kD = 1.3 in the cyclization using 5a-d0 and 5a-d1 (deuterated on the hydroxyl group) in separate experiments (see S1), which suggests that the cyclization (Int-1 to Int-2) is not the RDS. The small isotope effect observed may be ascribed to an equilibrium isotope effect. Negligible deuterium incorporation was observed in position 4, which is in contrast to the corresponding reaction with ruthenium.15 In summary, we have developed a diastereoselective synthesis of oxygen-containing heterocycles from readily available α-allenols via iron-carbene intermediates at ambient temperature. A number of substituted 2,3-dihydrofurans were obtained by this protocol. A computational study provides a deeper insight into the mechanism of the reaction. Further studies on the synthetic applications of the proposed carbene intermediate Int-3 are currently underway in our laboratory.
Importantly, we have also investigated the possibility that 2,5-dihydrofuran could be generated from a direct
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After completion of this work, Rueping and coworkers reported a related study on cycloisomerization of allenols based on our original work (ref 13).16 Their protocol gave 3,6-dihydro-2H-pyrane as the product with an iron complex at 70 oC. We have achieved cycloisomerization at ambient temperature with the air- and moisture-stable iron complex 1. In addition, the diastereoselective version of this type of cyclization was also explored in the present study. Figure 1. Calculated Free Energy Profile (energies are given in kcal/mol)
ASSOCIATED CONTENT AUTHOR INFORMATION Corresponding Author *
[email protected] *
[email protected] *
[email protected] Notes The authors declare no competing financial interest.
Supporting Information Experimental procedures and compound characterization data, including the 1H/13C NMR spectra, computational details, figures of intermediates and transition states, absolute energies and energy corrections, and Cartesian coordinates of optimized structures. This material is available free of charge via the Internet at http://pubs.acs.org.
ACKNOWLEDGMENT Financial support from the European Research Council (ERC AdG 247014), The Swedish Research Council (621-2013-4653),
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the Berzelii Center EXSELENT, and the Knut and Alice Wallenberg Foundation is gratefully acknowledged.
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