Communication pubs.acs.org/Organometallics
Ruthenium-Catalyzed Synthesis of cis-2,3-Dihydrobenzofuran-3-ols by Aqueous Transfer Hydrogenation via Dynamic Kinetic Resolution Lizhen Fang,* Saisai Liu, Lili Han, Huanhuan Li, and Fangfei Zhao School of Pharmacy, Xinxiang Medical University, Xinxiang 453003, Henan, People’s Republic of China S Supporting Information *
ABSTRACT: The preparation of cis-2,3-dihydrobenzofuranols with two stereocenters through aqueous asymmetric transfer hydrogenation (ATH) of benzofuranones with the metal catalyst Ru(II) via dynamic kinetic resolution (DKR) has been developed. A variety of α-alkyl benzofuranones were transformed to obtain optically pure 2,3-dihydrobenzofuran-3ols with excellent enantioselectivities and acceptable yields under mild conditions. We first explored DKR-ATH to obtain cis-2,3-dihydrobenzofurans using 2-(2-hydroxypropan-2-yl)benzofuran-3-(2H)-one (1a) as a model substrate under the conditions given in Table 1. During the pilot reaction, we noticed that the phase transfer catalyst (PTC) was critical; without the appropriate PTC, the reaction was difficult in various polar solvents miscible with water (Table 1, entries 1−4). However, when a PTC such as cetyltrimethylammonium bromide (CTAB) was used in the reaction, the reaction progressed smoothly, and the yield increased dramatically (Table 1, entry 5). Furthermore, in an organic solvent−water cosolvent medium, these reactions gave more satisfactory results, and optimization confirmed that CH2Cl2/H2O (1/1 v/v) was the optimal reaction solvent system (Table 1, entries 6, 7, and 9). The PTC was then examined in the subsequent reactions (Table 1, entries 8 and 10−15). The best result was achieved with CTAB (Table 1, entry 9). Except for β-CD, all of the other solvents could afford the desired products in moderate to high yields and with more than 90% ee. On the basis of the extensively studied chiral TsDPEN (N(p-toluenesulfonyl)-1,2-diphenylethylenediamine)-based organometallic complexes in the ATH reaction, the four commercially available organometallic complexes 4a (RuCl(pcymene)[(R,R)-TsDPEN]), 4b (RuCl[(R,R)-TsDPEN](mesitylene)), 4c (RuCl[(R,R)-Fsd-pen](p-cymene)), and 4d ((R)-RuCl[(p-cymene)(BINAP)]Cl) were screened to compare their catalytic performances. The results obtained with catalysts 4a−d (Table 1, entries 9 and 16−19) demonstrate that 4a was the best catalyst in this system. When 4b was used as a catalyst, DKR-ATH of 1a afforded the chiral products of 2a with a lower ee value. With 4c, an extremely high ee value was achieved, but a lower yield. Unexpectedly, with 4d, the reaction did not work, and starting materials were recovered (Table 1, entry 19). Interestingly, all of the reactions gave excellent
S
ubstituted 2,3-dihydrobenzofurans are present in numerous natural bioactive products and synthetic pharmacologically interesting compounds.1 To date, many methods have been developed to prepare these chiral 2,3-dihydrobenzofurans.2 However, most of them have been employed for the construction of trans-2,3-dihydrobenzo[b]furan only. Methods for fabricating the cis-2,3-dihydrobenzo[b]furan ring system are still scarce, and very few examples involving Rh(II)-catalyzed intramolecular C−H insertions3 and the intramolecular Michael addition/lactonization reaction4 have been reported. These methods seemed to be unsatisfactory from the standpoint of yield, selectivity, and generality. Additionally, hydrogenation of benzofuran derivatives to the corresponding 2,3-dihydrobenzofurans is one of the most straightforward methods to synthesize these compounds; however, it is still very difficult to carry out this hydrogenation using benzofuran compounds because of the partial cleavage of the furan ring.5 Recently, dynamic kinetic resolution through asymmetric transfer hydrogenation (DKR-ATH) has been used as a powerful methodology to construct two stereocenters to prepare various optically active compounds.6 We envisioned that DKR-ATH could also be used for the synthesis of chiral 2,3-dihydrobenzofuranol using a 2,3-dihydrobenzofuran αsubstituted ketone (Scheme 1), which is the crucial motif in numerous biologically active natural products and pharmaceuticals.7 In this paper, we report a mild, facile, and practical method to produce cis-2,3-dihydrobenzofuran-3-ols with high enantioselectivities. Scheme 1. DKR-ATH of Substituted Ketones
Received: January 11, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.organomet.7b00022 Organometallics XXXX, XXX, XXX−XXX
Communication
Organometallics Table 1. Optimization of Reaction Conditions for DKRATH of 2-(2-Hydroxypropan-2-yl)benzofuran-3(2H)-onea
entry
cat.
solvent
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
4a 4a 4a 4a 4a 4a 4a 4a 4a 4a 4a 4a 4a 4a 4a 4b 4b 4c 4d
i-PrOH (CH3)2CO THF MeOH MeOH CHCl3/H2O EtOAc/H2O EtOAc/H2O CH2Cl2/H2O CH2Cl2/H2O CH2Cl2/H2O CH2Cl2/H2O CH2Cl2/H2O CH2Cl2/H2O CH2Cl2/H2O CH2Cl2/H2O EtOAc/H2O CH2Cl2/H2O CH2Cl2/H2O
PTCb
yield of 2a (%)c
ee (%) of 2ad
dr (2a/3a)d
CTAB CTAB CTAB TAHS CTAB TBAB TTAC β-CD TBAC DTAC TAHS CTAB TAHS CTAB CTAB
0 0 0 1 41 48 63 69 87 43 52 52 70 74 80 86 67 70 0
0 0 0 >99 96 98 91 86 99 94 93 61 98 96 94 91 92 >99 0
0 0 0 97/3 >99/1 >99/1 >99/1 >99/1 >99/1 >99/1 >99/1 >99/1 >99/1 98/2 >99/1 >99/1 >99/1 >99/1 0
Table 2. DKR-ATH of 2-(2-Hydroxypropan-2yl)benzofuran-3-(2H)-one with Different Groups at the Benzene Ringa
isolated yield of 2 (%)b ee (%) of 2c
entry
2
R1
1 2 3 4 5 6 7 8 9 10
2a 2b 2c 2d 2e 2f 2g 2h 2i 2j
H 5-Cl 5-Br 5-OCH3 6-CH3 6-F 6-Cl 7-CH3 7-OCH3 7-Cl
87 50 80 52 74 83 62 63 55 73
99 99 94 88 >99 80 81 >99 >99 >99
dr (2/3)c >99/1 97/3 >99/1 >99/1 >99/1 >99/1 >99/1 >99/1 >99/1 98/2
The reactions were run on a 1.0 mmol scale in a 25 mL sealed flask under protection of argon. bIsolated yield including the minor enantiomer. cDetermined by HPLC analysis using a chiral column. a
8, and 9), but samples with such groups at the 5-position afforded products with lower ee values (Table 2, entry 4). We further investigated the general applicability with a series of benzofuran-3-(2H)-one analogues9 bearing different alkyl groups and alkyl groups with heterocyclic or aromatic groups at the 2-position (Table 3). The observations indicated that this DKR-ATH was suitable for constructing a wide scope of chiral 2,3-dihydrobenzofuran-3-ols with 2,3-distereocenters. Table 3. DKR-ATH of Benzofuran-3-(2H)-ones with Different Groups at the Furanone Ringa
a The reactions were run on a 1.0 mmol scale in a 25 mL sealed flask under protection of argon. The solvent amount was 4 mL, and the ratio of the cosolvents was 1/1. bAbbreviations: PTC, phase transfer catalyst; CTAB, cetyltrimethylammonium bromide; TAHS, tetrabutylammonium hydrogen sulfate; TBAB, tetrabutylammonium bromide; TTAC, trimethyltetradecylammonium chloride; TBAC, tetrabutylammonium chloride; β-CD, β-cyclodextrin; DTAC, dodecyltrimethylammonium chloride. cIsolated yield including the minor enantiomer. d Determined by HPLC analysis using a chiral column.
diastereoselectivities and the trans diastereomers 3a were very few. With these optimized conditions in hand, we examined the scope of 2-(2-hydroxypropan-2-yl)benzofuran-3-(2H)-one analogues (Table 2). Various substrates containing electronwithdrawing or electron-donating substituents at different positions of the benzene ring were first prepared by the reported procedures8 (see the Supporting Information). Reduction of these products under standard conditions resulted in all of the products being obtained in moderate to high yields with good or excellent ee values. It was also found that the electronic properties of the substituents of the Ar group affected their enantioselectivities: The substrates with electronwithdrawing groups at the 5-position of the benzofuran-3-one ring gave excellent ee values (Table 2, entries 2 and 3), while samples with these groups at the 6-position gave lower selectivity (Table 2, entries 6 and 7). Substrates with electron-donating groups at the 6- and 7-positions of benzofuran-3-one gave excellent ee values (Table 2, entries 5,
entry
6
R2
isolated yield of 6 (%)b
ee (%) of 6c
dr (6/7)c
1 2 3 4 5
6a 6b 6c 6d 6e
Me i-Pr 1-hydroxyethyl furan-2-ylmethyl PhCH2
59 35 50 42 68
94 98 95 85 97
>99/1 >99/1 98/2 >99/1 >99/1
a The reactions were run on a 1.0 mmol scale in a 25 mL sealed flask under protection of argon. bIsolated yield including the minor enantiomer. cDetermined by HPLC analysis using a chiral column.
The absolute configuration of 2i was assigned as (2R,3S)-2(2-hydroxypropan-2-yl)-7-methoxy-2,3-dihydrobenzofuran-3-ol by an X-ray diffraction analysis (Figure 1) and rationalized using the Noyori/Ikariya (R,R)-I catalyst as a model. On the basis of other previously reported work, we envisioned that the transfer hydrogenation of 2i10 and its analogues would proceed through the same well-known catalytic cycle.11 This mechanism has been described in many cases using the α-substituted ketones to prepare the α-halo alcohols,6b α-substituted βhydroxy ketones/esters/amides,12 β-amino-α-hydroxy esters,13 and so on.14 We also achieved total synthesis of the natural B
DOI: 10.1021/acs.organomet.7b00022 Organometallics XXXX, XXX, XXX−XXX
Communication
Organometallics
(3) Natori, Y.; Tsutsui, H.; Sato, N.; Nakamura, S.; Nambu, H.; Shiro, M.; Hashimoto, S. J. Org. Chem. 2009, 74, 4418−4421. (4) (a) Belmessieri, D.; Morrill, L. C.; Simal, C.; Slawin, A. M. Z.; Smith, A. D. J. Am. Chem. Soc. 2011, 133, 2714−2720. (b) Birman, V. B.; Li, X.-M. Org. Lett. 2006, 8, 1351−1354. (5) (a) Ortega, N.; Urban, S.; Beiring, B.; Glorius, F. Angew. Chem., Int. Ed. 2012, 51, 1710−1713. (b) Baralt, E.; Smith, S. J.; Hurwitz, J.; Horvath, I. T.; Fish, R. H. J. Am. Chem. Soc. 1992, 114, 5187−5196. (6) (a) Burling, S.; Whittlesey, M. K.; Williams, J. M. J. Adv. Synth. Catal. 2005, 347, 591−594. (b) Ros, A.; Magriz, A.; Dietrich, H.; Fernández, R.; Alvarez, E.; Lassaletta, J. M. Org. Lett. 2006, 8, 127− 130. (c) Fernández, R.; Ros, A.; Magriz, A.; Dietrich, H.; Lassaletta, J. M. Tetrahedron 2007, 63, 6755−6763. (d) Ros, A.; Magriz, A.; Dietrich, H.; Lassaletta, J. M.; Fernández, R. Tetrahedron 2007, 63, 7532−7537. (e) Peach, P.; Cross, D. J.; Kenny, J. A.; Mann, I.; Houson, I.; Campbell, L.; Walsgrove, T.; Wills, M. Tetrahedron 2006, 62, 1864−1876. (f) Echeverria, P. G.; Ayad, T.; Phansavath, P.; Ratovelomanana-Vidal, V. Synthesis 2016, 48, 2523−2539. (7) (a) Liu, G.; Lu, X. J. Am. Chem. Soc. 2006, 128, 16504−16505. (b) Yamada, S.; Iwaoka, A.; Fujita, Y.; Tsuzuki, S. Org. Lett. 2013, 15, 5994−5997. (c) Adams, T. E.; El Sous, M. E.; Hawkins, B. C.; Hirner, S.; Holloway, G.; Khoo, M. L.; Owen, D. J.; Paul Savage, G.; Scammells, P. J.; Rizzacasa, M. A. J. Am. Chem. Soc. 2009, 131, 1607− 1616. (d) Enders, D.; Niemeier, O.; Straver, L. Synlett 2006, 2006, 3399−3402. (8) Fang, L.-Z.; Han, L.-L.; Liu, S.-S.; Li, H.-H. Tetrahedron Lett. 2016, 57, 3315−3317. (9) (a) Farran, D.; Bertrand, P. Synth. Commun. 2012, 42, 989−1001. (b) Thapa, P.; Jahng, Y.; Park, P.-H.; Jee, J.-G.; Kwon, Y.; Lee, E.-S. Bull. Korean Chem. Soc. 2013, 34, 3073−3082. (c) Wallez, V.; DurieuxPoissonnier, S.; Chavatte, P.; Boutin, J. A.; Audinot, V.; Nicolas, J.-P.; Bennejean, C.; Delagrange, P.; Renard, P.; Lesieur, D. J. Med. Chem. 2002, 45, 2788−2800. (d) Kwon, H.-B.; Park, C.; Jeon, K.-H.; Lee, E.; Park, S.-E.; Jun, K.-Y.; Kadayat, T. M.; Thapa, P.; Karki, R.; Na, Y.; Park, M. S.; Rho, S. B.; Lee, E.-S.; Kwon, Y. J. Med. Chem. 2015, 58, 1100−1122. (10) CCDC 1506040 contains supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/ data_request/cif. (11) (a) Noyori, R.; Ikeda, T.; Ohkuma, T.; Widhalm, M.; Kitamura, M.; Takaya, H.; Akutagawa, S.; Sayo, N.; Saito, T.; Taketomi, T.; Kumobayashi, H. J. Am. Chem. Soc. 1989, 111, 9134−9135. (b) Genet, J. P.; Pinel, C.; Mallart, S.; Juge, S.; Thorimbert, S.; Laffitte, J. A. Tetrahedron: Asymmetry 1991, 2, 555−567. (c) Alnafta, N.; Schmidt, J. P.; Nesbitt, C. L.; McErlean, C. S. P. Org. Lett. 2016, 18, 6520−6522. (12) (a) Eustache, F.; Dalko, P. I.; Cossy, J. Org. Lett. 2002, 4, 1263− 1265. (b) Cartigny, D.; Püntener, K.; Ayad, T.; Scalone, M.; Ratovlmanana-Vidal, V. Org. Lett. 2010, 12, 3788−3791. (c) Seashore-Ludlow, B.; Saint-Dizier, F.; Somfai, P. Org. Lett. 2012, 14, 6334−6337. (13) (a) Villacrez, M.; Somfai, P. Tetrahedron Lett. 2013, 54, 5266− 5268. (b) Goodman, C. G.; Do, D. T.; Johnson, J. S. Org. Lett. 2013, 15, 2446−2449. (14) (a) Son, S.-M.; Lee, H.-K. J. J. Org. Chem. 2014, 79, 2666−2681. (b) Kim, J.-a.; Seo, Y. J.; Kang, S.; Han, J.; Lee, H.-K. Chem. Commun. 2014, 50, 13706−13709. (15) Fang, L.-Z.; Lyu, Q.-H.; Lu, C.-J.; Li, H.-H.; Liu, S.-S.; Han, L.-L. Adv. Synth. Catal. 2016, 358, 3196−3200.
Figure 1. Crystal structure of 2i with crystallographic numbering patterns. Displacement ellipsoids are drawn at the 30% probability level.
products daldinins with the benzofuran substrates by the DKRATH process.15 In conclusion, we developed a facile and efficient method to construct cis-2,3-dihydrobenzofurans by transfer hydrogenation of benzofuranones via DKR. The results showed that it is a mild, efficient route to obtain such chiral dihydrobenzofurans with excellent stereoselectivities, instead of the difficult to achieve hydrogenation of benzofurans.
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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.organomet.7b00022. Synthetic procedures for all compounds, 1H NMR and 13 C NMR spectra, HPLC chromatograms, and X-ray data (PDF) X-ray crystallographic data for 2i (CIF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail for L.F.: 2002fl
[email protected]. ORCID
Lizhen Fang: 0000-0001-8594-4710 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This project was sponsored by the National Natural Science Foundation of China (No. 81172952), the Foundation for University Key Teacher by the Education Department of Henan Province (2012, No. 137), and the program for Science & Technology Innovation Talents in Universities of Henan Province (17HASTIT043).
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REFERENCES
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DOI: 10.1021/acs.organomet.7b00022 Organometallics XXXX, XXX, XXX−XXX
