Letter pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Rhodium(I)-Catalyzed Enantioselective Hydroacylation of Racemic Allenals via Dynamic Kinetic Resolution Yoshihiro Oonishi,* Akihito Hosotani, Takayuki Yokoe, and Yoshihiro Sato* Faculty of Pharmaceutical Sciences, Hokkaido University, Nishi 6, Kita 12, Kita-ku, Sapporo 060-0812, Japan
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S Supporting Information *
ABSTRACT: Rhodium(I)-catalyzed enantioselective hydroacylation of 4-allenals was found to proceed smoothly, giving six-membered ketones in good yields (up to 84% yield) with high enantiomeric excess (up to 96% ee) even from racemic allenes as substrates. Mechanistic studies revealed that racemization of the allene moiety in the substrate would occur via a dynamic kinetic resolution (DKR) process during the hydroacylation.
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Scheme 1. Transition-Metal-Catalyzed Enantioselective Reaction of Internal Allenes as Substrates
llenes, which are cumulated dienes consisting of an sp carbon bonded to two other sp2 carbons, have received much attention from chemists because they have unique features, especially for transition-metal-catalyzed reactions, compared to alkenes.1 Over the past decade, there have been many reports on transition-metal-catalyzed reactions of terminal allenes, including enantioselective variants.1,2 However, there is a limit to the number of transition-metalcatalyzed enantioselective reactions using internal allenes as substrates because they are not prochiral but have an axial chirality (Scheme 1).3 For example, Willis reported rhodium(I)-catalyzed asymmetric hydroacylation using racemic allenes as substrates through a dynamic kinetic resolution (DKR), which includes rapid racemization of allenes and kinetic transformation of one of the enantiomers (eq 1). 3a Widenhoefer reported gold(I)-catalyzed intermolecular enantioselective hydroamination through racemization of allene.3b Four different types of rhodium(I)- or palladium(0)-catalyzed intermolecular reactions using racemic internal allenes as substrates were reported by Cramer3c and Breit groups.3d−f Despite the successful examples with respect to intermolecular reactions, the only example of a transition-metal-catalyzed intramolecular reaction of racemic allenes via a DKR process is gold(I)-catalyzed enantioselective intramolecular hydroamination of racemic allenes reported by Widenhoefer (eq 2).3g Furthermore, rhodium(I)-catalyzed intramolecular hydroacylation between an allene moiety and tethered aldehyde has not been reported so far, although hydroacylation is one of the most representative reactions that proceeds by a rhodium catalyst.4 Herein, we report the first rhodium(I)-catalyzed enantioselective intramolecular hydroacylation of racemic allenals via the DKR process.5−7 Initially, hydroacylation of racemic allene 1a was tested under various conditions (Table 1). The use of (R,R)-MeDuPHOS as a ligand, which was most efficient for asymmetric intermolecular hydroacylation of allenes reported by Willis (Scheme 1, eq 1),3a gave a complex mixture, although the starting material was completely consumed (entry 1). When © XXXX American Chemical Society
(R)-BINAP or (R)-Tol-BINAP was employed in this reaction, the desired cyclic compound 2a was produced in low yield and low enantioselectivity (entries 2 and 3). The use of (R)-H8Received: April 15, 2019
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DOI: 10.1021/acs.orglett.9b01307 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
benzonitrile showed almost the same effect as that of CH3CN. When 4-methoxybenzonitrile was used as an additive, the yield of 2a was dramatically decreased to 30%. On the other hand, aryl nitrile having an electron-withdrawing group at the para-position on the aromatic ring showed a high yield and high enantioselectivity. 4-Fluorobenzonitrile seemed to be the most effective for both the yield and ee of 2a. Furthermore, a catalytic amount of 4-fluorobenzonitrile was sufficient to promote the reaction, giving 2a in high yield with high enantioselectivity (e.g., 82% yield and 95% ee at 45 °C, 80% yield and 95% ee at rt). With the optimal conditions in hand, the scope and limitations of this reaction were tested (Scheme 3). 4-Allenal
Table 1. Hydroacylation of 4-Allenal 1a Using Various Ligands and Solventsa
entry
ligand
solvent
time (h)
yield (%)
ee (%)
1 2 3b 4b 5 6b 7 8 9c 10c,d
(R,R)-Me-DuPHOS (R)-BINAP (R)-Tol-BINAP (R)-H8-BINAP (R)-SEGPHOS (R)-DTBM-SEGPHOS (R)-DTBM-SEGPHOS (R)-DTBM-SEGPHOS (R)-DTBM-SEGPHOS (R)-DTBM-SEGPHOS
ClCH2CH2Cl ClCH2CH2Cl ClCH2CH2Cl ClCH2CH2Cl ClCH2CH2Cl ClCH2CH2Cl toluene acetone CH3CN acetone
23 1 33 5 22 15 10 28 44 19
18 25 24 52 62 68 19 72
33 19 28 69 71 75 93 90
Scheme 3. Enantioselective Hydroacylation of Various 4Allenals
a
[Rh(cod)2]BF4 (0.012 mmol), ligand (0.012 mmol), 1a (0.12 mmol), and solvent (1.2 mL) were employed. The cyclization was carried out at 65 °C (entries 1−7), 56 °C (entries 8 and 10), and 80 °C (entry 9). bThe cyclic compound 2a′ was obtained in 8% yield (entry 3), 80% yield (entry 4), and 2% yield (entry 6). c1a was recovered in 22% yield (entry 9) and 4% yield (entry 10). dCH3CN (3 equiv) was used as an additive.
BINAP afforded the cyclic compound 2a′, which would be produced through isomerization of 2a (entry 4). Next, SEGPHOS-type ligands were tested in this cyclization (entries 5 and 6). When (R)-DTBM-SEGPHOS was used as a ligand, the ee of the cyclic compound 2a was improved to 69%, but the yield was modest (entry 6). Next, screening of solvents by using (R)-DTBM-SEGPHOS as a ligand was carried out (entries 7−9). It was found that the use of acetone as a solvent improved the yield and ee of 2a, while CH3CN showed high ee, though the yield of 2a was low. Surprisingly, the cyclization of 1a in acetone with 3 equiv of CH3CN as an additive gave 2a in 72% yield with 90% ee (entry 10). The results indicate that the existence of CH3CN strongly affects the enantioselectivity in the cyclization. Thus, various nitriles as additives were screened in hydroacylation of 1a, and the results are summarized in Scheme 2.8 The use of 1b afforded the corresponding cyclic compound 2b in moderate yield and enantioselectivity. The ester group and phthalimide moiety were also tolerated in this cyclization, and the cyclic compounds 2c−2e were obtained in good yields and moderate ee’s. On the other hand, hydroacylation of 4-allenals 1f−1h proceeded to give six-membered ketones 2f−2h in good yields and high ee’s.9 In the case of 4-allenal 1i having tbutyl on the allene moiety, the ee of 2i was 96%, although the yield was moderate, probably due to the steric hindrance around the allene moiety. When 4-allenals 1j−1l having an aromatic ring on the allene moiety were used as substrates, cyclic ketones 2j−2l were produced in moderate yields and high enantioselectivity. 4-Allenal 1m having a triisopropyl silyl group at the terminus of allene could be used for this reaction, although its yield and ee were not satisfactory. In order to gain insight into the mechanism, additional experiments were carried out (Scheme 4). First, the reaction of 1a-D was carried out under the optimized conditions, giving the corresponding product 2a-D, having a deuterium on the alkene moiety, in a high yield and high ee with a high D-
Scheme 2. Hydroacylation of 4-Allenal 1a Using Various Nitrilesa
a
[Rh(cod)2]BF4 (0.012 mmol), ligand (0.012 mmol), 1a (0.12 mmol), and acetone (1.2 mL) were employed. b1a was recovered in 4% yield (acetonitrile) and 24% yield (4-methoxybenzonitrile). B
DOI: 10.1021/acs.orglett.9b01307 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
reaction of (S)-1f gave the cyclic product (S)-2f in 74% yield with 33% ee. This result suggests that a chirality transfer from chiral allene (S)-1f to the product partially occurs to give (S)2f as a major enantiomer; however, racemization of the allene moiety may also occur during the cyclization, resulting in a decrease in the ee of the product. Finally, hydroacylation of the enantiomerically enriched (S)-1f using (R)- or (S)-DTBMSEGPHOS as a ligand was carried out (eqs 4 and 5). The reaction of (S)-1f using (R)-DTBM-SEGPHOS proceeded smoothly (6 h at 45 °C) to give 2f, having an S configuration, in 83% yield with 92% ee. On the other hand, the reaction of (S)-1f using (S)-DTBM-SEGPHOS needed a longer time to consume (S)-1f (96 h at 45 °C) and gave the opposite enantiomer, (R)-2f, in 68% yield with 81% ee. These results indicate that the absolute configuration of product 2f is completely controlled by the chirality of the ligand. Furthermore, the longer reaction time and slight decrease of the product’s ee by using (S)-DTBM-SEGPHOS suggest that the combination of (S)-allene and (S)-ligand (or (R)-allene and (R)-ligand) would be a mismatched pair, while the combination of (S)-allene and (R)-ligand (or (R)-allene and (S)-ligand) would be a matched pair in the hydroacylation. A possible reaction mechanism that can explain the results of the above-mentioned mechanistic experiments is depicted in Scheme 5. As mentioned above,2a,c chiral oxo-rhodacycle intermediate (S)-iv would be formed from (S)-1 in a stereospecific manner, giving (S)-2 through reductive elimination from (S)-iv. Also, (R)-2 would be produced from (R)-1 via oxo-rhodacycle (R)-iv. These reaction pathways are consistent with the deuterium-labeling experiment (Scheme 4, eq 1). From mechanistic studies of eqs 4 and 5 in Scheme 4, the combination of (S)-1 and (R)-DTBM-SEGPHOS should be a matched pair, so (S)-2 from (S)-1 was smoothly produced via the favored pathway by using (R)-DTBM-SEGPHOS. On the other hand, the reaction of (R)-1 with (R)-DTBMSEGPHOS would be mismatched, in which case racemization of (R)-1 to (S)-1 would occur before cyclization via the disfavored pathway (mismatched) in Scheme 5. According to the result of eq 5 in Scheme 4, racemization between (S)-1 and (R)-1 actually occurs under the cyclization conditions. Thus, (S)-2 was obtained in high yield and high ee even from racemic allene 1 by using (R)-DTBM-SEGPHOS in this reaction. Besides, the use of nitrile as an additive improved the yield and ee of 2a and shortened the reaction time, as shown in
Scheme 4. Mechanistic Studies
content (eq 1). Second, the reaction of enantiomerically enriched (S)-1f (>99% ee) with a rhodium complex, having an achiral ligand, BIPHEP, was examined (eq 2). In our previous studies on rhodium(I)-catalyzed [6 + 2] cycloaddition,2a,c the reaction of 4-allenal (S)-1a (91% ee) with alkyne 3 gave eightmembered product (S)-4 in 81% yield with 89% ee (eq 3), indicating that the chiral oxo-rhodacycle intermediate (S)-iv was stereospecifically formed from chiral allene (S)-1a with an almost perfect chirality transfer. On the other hand, the Scheme 5. Possible Reaction Mechanism
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DOI: 10.1021/acs.orglett.9b01307 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
Synth. Catal. 2011, 353, 2561. (i) Krause, N.; Winter, C. Chem. Rev. 2011, 111, 1994 and references therein . (2) For our recent studies on transition-metal-catalyzed reactions of allenes, see: (a) Oonishi, Y.; Hosotani, A.; Sato, Y. J. Am. Chem. Soc. 2011, 133, 10386. (b) Oonishi, Y.; Kitano, Y.; Sato, Y. Angew. Chem., Int. Ed. 2012, 51, 7305. (c) Oonishi, Y.; Hosotani, A.; Sato, Y. Angew. Chem., Int. Ed. 2012, 51, 11548. (d) Oonishi, Y.; Kitano, Y.; Sato, Y. Tetrahedron 2013, 69, 7713. (e) Oonishi, Y.; Yokoe, T.; Hosotani, A.; Sato, Y. Angew. Chem., Int. Ed. 2014, 53, 1135. (f) Oonishi, Y.; Saito, A.; Sato, Y. Asian J. Org. Chem. 2015, 4, 81. (g) Oonishi, Y.; Hato, Y.; Sato, Y. Adv. Synth. Catal. 2015, 357, 3033. (h) Saito, N.; Kohyama, Y.; Tanaka, Y.; Sato, Y. Chem. Commun. 2012, 48, 3754. (i) Saito, N.; Ichimaru, T.; Sato, Y. Chem. - Asian J. 2012, 7, 1521. (j) Takimoto, M.; Kawamura, M.; Mori, M.; Sato, Y. Synlett 2011, 2011, 1423. (3) (a) Osborne, J. D.; Randell-Sly, H. E.; Currie, G. S.; Cowley, A. R.; Willis, M. C. J. Am. Chem. Soc. 2008, 130, 17232. (b) Butler, K. L.; Tragni, M.; Widenhoefer, R. A. Angew. Chem., Int. Ed. 2012, 51, 5175. (c) Tran, D. N.; Cramer, N. Angew. Chem., Int. Ed. 2013, 52, 10630. (d) Pritzius, A. B.; Breit, B. Angew. Chem., Int. Ed. 2015, 54, 15818. (e) Grugel, C. P.; Breit, B. Chem. - Eur. J. 2018, 24, 15223. (f) Hilpert, L. J.; Sieger, S. V.; Haydl, A. M.; Breit, B. Angew. Chem., Int. Ed. 2019, 58, 3378. (g) Zhang, Z.; Bender, C. F.; Widenhoefer, R. A. J. Am. Chem. Soc. 2007, 129, 14148. For selected examples of Pd(0)catalyzed asymmetric allylic alkylation of internal allenes, see: (h) Imada, Y.; Ueno, K.; Kutsuwa, K.; Murahashi, S.-I. Chem. Lett. 2002, 31, 140. (i) Trost, B. M.; Fandrick, D. R.; Dinh, D. C. J. Am. Chem. Soc. 2005, 127, 14186. (4) We previously found rhodium(I)-catalyzed hydroacylation of allenal during study on [6 + 2] cycloaddition. However, the yield of the six-membered cyclic compound was low (20% yield). See ref 2a. (5) For a selected review, see: Willis, M. C. Chem. Rev. 2010, 110, 725 and references therein . (6) For the synthesis of a six-membered ring by rhodium(I)catalyzed intramolecular hydroacylation, see: (a) Gable, K. P.; Benz, G. A. Tetrahedron Lett. 1991, 32, 3473. (b) Nicolaou, K. C.; Gross, J. L.; Kerr, M. A. J. Heterocycl. Chem. 1996, 33, 735. (c) Takeishi, K.; Sugishima, K.; Sasaki, K.; Tanaka, K. Chem. - Eur. J. 2004, 10, 5681. (7) For the selected examples of synthesis of nonconjugated cyclohexones by rhodium(I)-catalyzed cyclization, see: (a) Kurahashi, T.; de Meijere, A. Synlett 2005, 2619. (b) Jiang, G.-J.; Fu, X.-F.; Li, Q.; Yu, Z.-X. Org. Lett. 2012, 14, 692. (c) Shu, D.; Li, X.; Zhang, M.; Robichaux, P. J.; Tang, W. Angew. Chem., Int. Ed. 2011, 50, 1346. (d) Shu, D.; Li, X.; Zhang, M.; Robichaux, P. J.; Guzei, I. A.; Tang, W. J. Org. Chem. 2012, 77, 6463. (e) Zhang, M.; Tang, W. Org. Lett. 2012, 14, 3756. (f) Liu, C.-H.; Yu, Z.-X. Org. Biomol. Chem. 2016, 14, 5945. (g) Wang, L.-N.; Cui, Q.; Yu, Z.-X. J. Org. Chem. 2016, 81, 10165. (8) For rhodium(I)-catalyzed hydroacylation using nitirle as an additive, see: (a) Imai, M.; Tanaka, M.; Nagumo, S.; Kawahara, S.; Suemune, H. J. Org. Chem. 2007, 72, 2543. (b) Chaplin, A. B.; Hooper, J. F.; Weller, A. S.; Willis, M. C. J. Am. Chem. Soc. 2012, 134, 4885. (9) The absolute configuration of 2f was assigned after chemical transformation (see Supporting Information). (10) Racemization of allenes catalyzed by Rh−H species was reported by several groups.3c,d From these studies, the similar racemization also seems to occur in the present cyclization even though it is not clear how their species are generated at this stage.
Scheme 6. Although the role of nitrile in this reaction is still unclear, we speculated that nitrile could accelerate racemization of the allene and/or reductive elimination from (S)-iv.10 Scheme 6. Effect of Nitrile on Hydroacylation of 1a
In conclusion, we have developed rhodium(I)-catalyzed enantioselective hydroacylation of 4-allenals for the first time, giving various six-membered cyclic ketones in high yields and high ee’s. Several mechanistic studies revealed that rapid racemization of the allene moiety in the substrate occurs via a dynamic kinetic resolution (DKR) process during the hydroacylation. The results should provide a new way for synthesis of chiral cyclic compounds from the racemic internal allenes. Further studies to determine the scope, limitations, and the detailed mechanism of this reaction are in progress.
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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.9b01307. Complete experimental procedures and characterization data for the prepared compounds (PDF)
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Yoshihiro Oonishi: 0000-0002-0323-8642 Yoshihiro Sato: 0000-0003-2540-5525 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was financially supported by Grants-in-Aid for Scientific Research (B) (No. 26293001) and Grants-in-Aid for Scientific Research (C) (No. 17K08202) from JSPS. We thank Takasago International Corporation for the gift of (R)-TolBINAP, (R)-H8-BINAP, (R)-SEGPHOS, and (R)-DTBMSEGPHOS.
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REFERENCES
(1) For selected reviews on transition-metal-catalyzed reactions of allenes, see: (a) Lledó, A.; Pla-Quintana, A.; Roglans, A. Chem. Soc. Rev. 2016, 45, 2010. (b) Kitagaki, S.; Inagaki, F.; Mukai, C. Chem. Soc. Rev. 2014, 43, 2956. (c) López, F.; Mascareñas, J. L. Chem. Soc. Rev. 2014, 43, 2904. (d) Alonso, J. M.; Quiros, M. T.; Muñoz, M. P. Org. Chem. Front. 2016, 3, 1186. (e) Muñoz, M. P. Chem. Soc. Rev. 2014, 43, 3164. (f) Muñoz, M. P. Org. Biomol. Chem. 2012, 10, 3584. (g) Aubert, C.; Fensterbank, L.; Garcia, P.; Malacria, M.; Simonneau, A. Chem. Rev. 2011, 111, 1954. (h) Alcaide, B.; Almendros, P. Adv. D
DOI: 10.1021/acs.orglett.9b01307 Org. Lett. XXXX, XXX, XXX−XXX
