Qi
Zhang
and
Hien M.
Nguyen
*
University of Iowa, Department of Chemistry, Iowa City, IA 52242, USA. E-mail: hien-nguyen@uiowa.edu
First published on 3rd October 2013
A highly regioselective rhodium-catalyzed ring-opening of vinyl epoxides with Et3N·3HF reagent to form branched allylic fluorohydrins is described. The reaction occurs at room temperature under ambient air and relies on RhCOD2BF4 as an effective catalyst, providing the desired 1,2-addition allylic fluorohydrins in moderate to good yields with excellent levels of regioselectivity. Mechanistic studies demonstrate that the regioselective ring-opening of enantiopure vinyl epoxide occurs with inversion of stereochemistry.
Vinyl epoxides are commonly used building blocks for the synthesis of biologically active targets.7 They are quite reactive in the presence of transition-metal catalysts.8 Palladium is most frequently used to promote the ring-opening of vinyl epoxides with a wide variety of nucleophiles, leading to 1,4-addition products due to the electron-deficient nature of the vinyl epoxide oxygen.9 The 1,2-addition products can be achieved by choice of the ligand and co-catalysts.10 Rhodium has also been reported as an effective catalyst for the ring-opening of vinyl epoxides with both anilines and alcohols to provide trans-1,2-amino alcohols or alkoxy alcohols, respectively, in good yield and with high levels of diastereo- and regio-selectivity.11 Even though the transition-metal-catalyzed asymmetric ring-opening of terminal epoxides1e,12 and oxabicyclic olefins13 using the nucleophilic fluoride ion has been developed, to the best of our knowledge there are no reports on the transition-metal-catalyzed regioselective ring-opening of vinyl epoxides with nucleophilic fluoride reagents.14
Entry | Catalyst | Loading (mol%) | F source | Solvent | Time (h) | NMR yield 2Ab (%) | Isolated yield 2c (%) |
---|---|---|---|---|---|---|---|
a All reactions were conducted with 0.2 mmol of vinyl epoxide 1. b The NMR yield of allylic fluorohydrin 2A was determined by 19F NMR analysis of the crude reaction mixture using PhCF3 as an internal standard. c For full analyses, crude product 2A was then transformed into the isolable allylic 4-fluorobenzoate 2 and the isolated yield was determined. d The reaction was performed with 10 mmol of vinyl epoxide 1. | |||||||
1 | [IrCl(COD)]2 | 2.5 | Et3N·3HF | Et2O | 2 | 37 | |
2 | [RhCl(COD)]2 | 2.5 | Et3N·3HF | Et2O | 2 | 55 | |
3 | RhCOD2OTf | 5 | Et3N·3HF | Et2O | 0.5 | 70 | |
4 | RhCOD2BF4 | 5 | Et3N·3HF | Et2O | 0.5 | 88 | |
5 | RhCOD2BF4 | 5 | Et3N·3HF | MTBE | 0.5 | 71 | |
6 | RhCOD2BF4 | 5 | Et3N·3HF | CH2Cl2 | 0.5 | 79 | |
7 | RhCOD2BF4 | 5 | Et3N·3HF | THF | 0.5 | 92 | |
8 | None | 0 | Et3N·3HF | Et2O | 18 | 23 | |
9 | None | 0 | Et3N·3HF | THF | 18 | 35 | |
10 | RhCOD2BF4 | 5 | Pyridine·HF | THF | 14 | 12 | |
11 | RhCOD2BF4 | 5 | CsF | THF | 18 | 0 | |
12 | RhCOD2BF4 | 5 | TBAT | THF | 18 | 0 | |
13 | RhCOD2BF4 | 5 | AgF | THF | 18 | 0 | |
14 | RhCOD2BF4 | 5 | KF | THF | 18 | 0 | |
15 | RhCOD2BF4 | 5 | Et3N·3HF | Et2O | 0.5 | 89 (88)d | 79 (76)d |
With the optimized conditions in hand, we proceeded to explore the scope and limitation of the rhodium-catalyzed regioselective ring-opening of vinyl epoxides (Table 2). We discovered that five- and seven-membered ring vinyl epoxides performed poorly under the same reaction protocol. We reasoned that acyclic vinyl epoxides possessing greater conformational flexibility may undergo ring-opening in the presence of RhCOD2BF4 and Et3N·3HF reagent. To our excitement, various acylic vinyl epoxide substrates 3–13 (Table 2) proceeded smoothly under rhodium conditions. Because most epoxide substrates are too volatile for isolation, all allylic fluorohydrins 14A–24A were converted into the 4-fluoro-benzoate derivatives 14–24 for full analyses and isolated yield calculation. Overall, the reactivity of the vinyl epoxides is dependent on both the steric and electronic nature of the substituents at the C(1)- and C(2)-position of the allyl moiety. For instance, the presence of the methyl group at the C(2)-position of vinyl epoxides 3 and 4 (Table 2, entries 1 and 2) provided allylic fluorides 14 and 15 in 60% and 62% yield, respectively, compared to their epoxide counterparts 5–8 (43–58%, entries 3–6). We discovered that vinyl epoxides containing the C(1)-electron-donating groups (e.g. 4-methoxy-phenyl) only resulted in decomposition. In contrast, electron-withdrawing substituents at the C(1)-position of vinyl epoxides 4–7 (entries 2–5) provided allylic fluorohydrins 15A–18A in 50–76% NMR yield (43–62% of their isolable fluoride derivatives). On the other hand, increasing the steric hindrance at the C(2)-position (entry 7) requires a significantly longer reaction time (10 h vs. 1 h) and allylic fluoride 20 was isolated in 59% yield. Vinyl epoxide 10 (entry 8) bearing the primary alkyl functionality also performed adequately to provide the allylic fluorohydrin 21A in 61% NMR yield.
Entry | Vinyl epoxides | Time (h) | Allylic fluorohydrins NMR yielda | Allylic fluorides isolated yield |
---|---|---|---|---|
a NMR yields of allylic fluorohydrins 14A–24A were determined by 19F NMR analysis of the reaction mixture using PhCF3 as an internal standard.
b Reactions were performed using 0.2 mmol of vinyl epoxides.
c Reactions were performed using 0.5 mmol of vinyl epoxides.
d An 11![]() ![]() ![]() ![]() ![]() ![]() |
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1 | 3: R = H | 1 | 14A (82%)d | 14 (60%)b |
2 | 4: R = Cl | 1 | 15A (76%)d | 15 (62%)c |
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3 | 5: R = 4-Cl | 1 | 16A (64%) | 16 (46%)b |
4 | 6: R = 3-Br | 1 | 17A (63%) | 17 (43%)c |
5 | 7: R = 4-CF3 | 4 | 18A (50%) | 18 (46%)b |
6 | 8: R = H | 1 | 19A (69%) | 19 (58%)b |
7 |
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10 | 20A (73%)e | 20 (59%)b |
8 |
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3 | 21A (61%)f | 21 (48%)b |
9 |
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1 | 22A (50%) | 22 (49%)b |
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22A (50%) | 22 (44%)c | ||
10 | 12: R = H | 0.5 | 23A (80%) | 23 (70%)b |
11 | 13: R = Me | 0.5 | 24A (65%) | 24 (56%)b |
The success of butadiene monoepoxide 11 (Table 2, entry 9) to form fluorohydrin 22A (50% NMR yield) and its isolable fluoride 22 (44–49%) led to our studies of isoprene monoepoxide 12 (entry 10) and C(2)-substituted methyl substrate 13 (entry 11). The reactions were fast (0.5 h) and proceeded with complete regioselectivity, providing tertiary allylic fluorohydrins 23A and 24A, respectively, in good NMR yields (65–80%). As expected, the more hindered vinyl epoxide 13 provided allylic fluorohydrin 24A in lower yield than that of substrate 12. These results are consistent with what has been observed when comparing the ring-opening of vinyl epoxide 3 (entry 1) to that of the more hindered 9 (entry 7), where the NMR yield is 82% vs. 73%.
With the ability to access a number of allylic fluorohydrins in moderate to good yields and with excellent regioselectivity, we next sought to establish the utility of this method by transforming tertiary allylic fluorohydrins into the tertiary alkyl fluorides 25 and 26 (Scheme 2), which could be potentially used as structural motifs of anticancer ether phospholipid compounds.18 One-pot regioselective ring-opening of vinyl epoxides 12 and 13 followed by hydrogenation and benzoylation furnished tertiary fluorides 25 and 26 in 52% and 50% yield, respectively.
To determine if Lewis acid behavior alone was responsible for reactivity with RhCOD2BF4, we conducted control experiments with cyclohexyl epoxide 27 and styrene oxide 28 (Scheme 3) under the same rhodium conditions. No products were observed after 18 h, suggesting that RhCOD2BF4 is likely not acting as a Lewis acid and the presence of an alkene unit is required for the reaction to occur. These results are consistent with previously reported results for the rhodium-catalyzed regioselective ring-opening of vinyl epoxides with alcohols and anilines.11
To gain some mechanistic insight, enantiopure epoxide (S)-11 was subjected to standard rhodium conditions (Scheme 4a). Allylic fluoride 22 was isolated in 43% yield with 69% ee. When the ring opening of (S)-11 was conducted in the absence of the catalyst, 22 was isolated in only 14% yield, albeit with a higher enantioselectivity (80% ee).14b,19,20 On the other hand, opening of enantiopure epoxide (R)-8 containing the C(1)-phenyl group, with and without the rhodium catalyst (Scheme 4b), resulted in significant racemization of allylic fluoride 19 (10–13% ee).
To establish the absolute stereochemistry of the allylic fluoride product, 22 was subjected to cross-metathesis with 4-bromo-styrene 29 (Scheme 5). The major enantiomer of diene product 30 (67% ee) was shown by X-ray crystallographic analysis to be R-configured.20 Collectively, the data illustrates that the rhodium-catalyzed regioselective opening of vinyl epoxide with Et3N·3HF proceeds with inversion of stereochemical configuration.21 This is opposite to what has been reported for palladium-catalyzed allylic fluorination.5a,f
Based on the results obtained in Schemes 4 and 5, we propose the following mechanistic rationale for the regioselective ring-opening of vinyl epoxides lacking the C(1)-functional group.22 The rhodium catalyst first coordinates to the olefin of (S)-11 to form rhodium–alkene complex 31 (Scheme 6). Subsequent ionization of 31 provides the π-allylrhodium intermediate 32.23 We hypothesize that hydrogen fluoride may first attack the rhodium center of 32 to form the corresponding fluoride–rhodium complex 33. Fluoride is widely regarded as a hard nucleophile,24 which has been known to bind to the metal center of the allyl–metal complex in allylic substitution.25 Protonation of the alkoxide followed by reductive elimination and benzoylation affords the corresponding (R)-allylic fluoride 22 with retention of stereochemistry, which is confirmed by X-ray crystallographic analysis.20 To rationalize the excellent levels of regioselectivity for the 1,2-addition products, we hypothesize that the fluoride ion selectively attacks the more substituted allyl position of 34. Because (R)-22 was generated in 69% ee (Scheme 4a), we propose that nucleophilic attack by fluoride onto the π-allylrhodium complex 32 (Scheme 6) must occur faster than isomerization of complex 32 to its corresponding ent-32. Alternatively, the erosion of enantioselectivity observed in product 22 could arise if the allylic fluorohydrin intermediate is undergoing a degenerate substitution reaction with the Et3N·3HF reagent.26
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Scheme 6 Proposed mechanism for rhodium-catalyzed ring-opening of vinyl epoxides lacking the C(1)-substituent. |
Footnote |
† Electronic supplementary information (ESI) available: Experimental procedures, characterization data for all new compounds. CCDC 964273. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c3sc51949j |
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