DOI: 10.1002/asia.201403196
Communication
Copper Catalysis
Copper-Catalyzed Aerobic C C Bond Cleavage of Lactols with NHydroxy Phthalimide for Synthesis of Lactones Ya Lin Tnay and Shunsuke Chiba*[a] Abstract: The transformation of cyclic hemiacetals (lactols) into lactones has been achieved by Cu-catalyzed aerobic C C bond cleavage in the presence of N-hydroxy phthalimide (NHPI). The present process is composed of a multistep sequence including a) formation of exo-cyclic enol ethers by dehydration; b) addition of phthalimide N-oxyl radical to the enol ethers followed by trapping of the resulting C-radicals with molecular oxygen to form peroxy radicals; c) reductive generation of oxy radicals and subsequent b-radical fragmentation to generate lactones.
Molecular transformations involving fission of inert C C bonds provide new methods for the synthetic design of the target molecules. Therefore, a variety of methods realizing efficient C C bond cleavage and functionalization have been exploited, in which catalytic processes using transition metals [M] are a recent main trend in the method development.[1] These reactions are commonly driven by release of ring strain, diminution of steric congestion, or generation of a relatively stable C [M] bond as the driving force of the inert C C bond cleavage. Our group has been working on the development of aliphatic C H oxidation using hetero-atom radicals generated under Cu-catalyzed aerobic reaction conditions.[2, 3] In this context, we recently disclosed a Cu-catalyzed aerobic oxygenation of aliphatic C H bonds through 1,5-H radical transfer of the oxygen-centered radical generated from peroxy derivatives (Scheme 1).[4, 5] For example, the reaction of alkane 1,1-diphenylpentane under Cu-catalyzed aerobic reaction conditions in the presence of N-hydroxyphthalimide (NHPI) delivered lactol 1 a in 41 % yield after 24 h. This alkane oxygenation takes place through a step-wise radical sequence involving 1) phthalimide N-oxyl radical-mediated intermolecular benzylic C H oxygenation with molecular oxygen (at the carbon marked in green); 2) generation of oxygen-centered radical and its 1,5-H radical abstraction (at the carbon marked in red) followed by aerobic oxygenation (Scheme 1). During the course of this
Scheme 1. Preliminary finding for the formation of lactone 2 a by oxidative C C bond cleavage from 1 a.
study, it was surprisingly found that prolonging the reaction time to 36 h gave rise to another product, namely, a,b-unsaturated lactone 2 a in 19 % yield along 1 a in 26 % yield. It was assumed that a,b-unsaturated lactone 2 a was formed from lactol 1 a through an unstrained C Me bond cleavage as well as a,b-unsaturation under the present reaction conditions. We therefore became interested in this unprecedented molecular transformation and aimed at developing a new chemical transformation of lactols to the corresponding lactones by the C C bond fission. Optimization of the reaction conditions and scope of the reaction as well as the detailed reaction mechanism are described herein. We began our investigation using lactol 1 a[6] to optimize the reaction conditions for the synthesis of lactone 2 a (Table 1). It was found that the presence of Cu-catalysts, NHPI, and molecular O2 was essential for the reaction to occur. Indeed, treatment of lactol 1 a with CuCl (20 mol %) and NHPI A (1 equiv) in MeCN under an O2 atmosphere at 50 8C provided a,b-unsaturated lactone 2 a in 49 % yield (Table 1, entry 1). Raising the reaction temperature to 80 8C improved the yield of 2 a to 71 % yield (Table 1, entry 2). Screening the Cu salts and solvents revealed that the reaction performs best with CuCl in
[a] Y. L. Tnay, Prof. S. Chiba Division of Chemistry and Biological Chemistry School of Physical and Mathematical Sciences Nanyang Technological University Singapore 637371 (Singapore) E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/asia.201403196. Chem. Asian J. 2014, 00, 0 – 0
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Communication Table 1. Optimization of the reaction conditions.[a]
Entry
[Cu] (mol %)
Additive [equiv]
Solvent
T [8C]
t [h]
Yield [%]
1 2 3 4 5 6 7 8[b] 9 10 11 12
CuCl (20) CuCl (20) CuBr (20) CuI (20) Cu(OAc)2 (20) CuCl (20) CuCl (20) CuCl (10) CuCl (5) CuCl (20) CuCl (20) CuCl (20)
A (1) A (1) A (1) A (1) A (1) A (1) A (1) A (1) A (1) B (1) C (1) D (1)
MeCN MeCN MeCN MeCN MeCN EtOAc DMSO MeCN MeCN MeCN MeCN MeCN
50 80 80 80 80 80 80 80 80 80 80 80
7 6 19 19 19 20 24 12 24 48 48 24
49 71 50 11 11 55 64 72 72 45 13 0
Scheme 2. Synthetic scope of a,b-unsaturated-g-butyrolactones 2. [a] Lactols 1 except for 1 k exist as an equilibrium mixture with their acyclic forms, ghydroxy ketones (see the Supporting Information for more details).
[a] The reactions were carried out using 0.5 mmol of 1 a in 5 mL of solvent (0.1 m) under an O2 atmosphere (1 atm). Lactol 1 a exists as an equilibrium mixture with its acyclic form, g-hydroxy ketone (see the Supporting Information for more details). [b] Phthalimide (3) was isolated in 20 % yield.
Scheme 3. The reaction of d-hydroxy ketone 1 l.
product, which is likely formed through dehydration followed by subsequent allylic oxygenation. The effect of the hemiacetal substituent R4 was then examined (Table 2). Changing the methyl group (1 a) to ethyl (1 aa) and isopropyl (1 ab) lowered the mass-balance of the products (Table 2, entries 1 and 2), but intriguingly delivered not only a,b-unsaturated lactone 2 a but also a,b-saturated lactone (gbutyrolactone) 5 a in the ratio of about 2:1. The reaction with
MeCN (Table 1, entries 3–7). The catalyst loading of CuCl could be lowered to 5 mol % while maintaining the yield of 2 a, albeit with a longer reaction time (Table 1, entries 8 and 9). It is noteworthy that in the reaction using 10 mol % CuCl and one equivalent of NHPI, phthalimide (3) was isolated in 20 % yield (Table 1, entry 8).[7] The effect of additives was next examined. Use of N-hydroxysuccinimide B or N-hydroxybenzotriazole C, instead of NHPI A, was not optimal for the present transformation (Table 1, entries 10 and 11). Lactone 2 a was not formed in the reaction with TEMPO D (Table 1, entry 12). Having optimized the reaction conditions (Table 1, entry 8 with 10 mol % of CuCl), we next investigated the substrate scope of hemiacetals 1 (Scheme 2). It was found that the g-position should be fully substituted (R1 and R2) to enable the present catalytic C C bond fission and a,b-unsaturation for the synthesis of lactone 2.[8] Various aryl groups including a thienyl moiety could be installed at the g-position to afford the corresponding lactone 2 in good to moderate yields. The reactions of g-dialkyl lactols 1 i and 1 j also proceeded to afford the corresponding a,b-unsaturated lactones 2 i and 2 j in acceptable yields, respectively. Installation of a methyl group at the b-position (R3) did not disturb the process, thereby affording lactone 2 k in 62 % yield. The reaction of d-hydroxy ketone 1 l (that is observed as a sole acyclic form without 6-membered ring hemiacetal) under the present reaction conditions delivered the desired a,b-unsaturated lactone 2 l in only 22 % yield (Scheme 3). In this case, 1,3-diketone 4 l was isolated in 23 % yield as a major &
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Table 2. Effect of hemiacetal substituent for the formation of lactones 2 a and 5 a.[a]
Entry 1 2 3[b] 4 5 6 7
1 (R4) 4
1 aa (R = Et) 1 ab (R4 = iPr) 1 ac (R4 = Ph) 1 ad (R4 = CH2OBn) 1 ae (R4 = CH2OMe) 1 ae (R4 = CH2OMe) 1 af (R4 = CH2OTBS)
T [8C]
t [h]
2 a [%]
5 a [%]
80 80 80 80 80 50 50
7 3 8 48 24 72 168
25 24 0 20 8 5 1
13 10 0 60 52 70 61
[a] The reactions were carried out using 0.5 mmol of 1 a in 5 mL of solvent (0.1 m) under an O2 atmosphere (1 atm). Lactols 1 (except for 1 ac) exist as an equilibrium mixture with their acyclic forms, g-hydroxy ketones (see the Supporting Information for more details). [b] 1 ac is observed as a sole acyclic form without its lactol form (see the Supporting Information for more details).
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Communication lactol 1 ac with a phenyl group was unsuccessful (Table 2, entry 3). It is noteworthy that the reactions with lactols 1 ad– 1 af bearing alkoxymethyl functions as R4 delivered saturated g-butyrolactone 5 a as a major product despite longer reaction times (Table 2, entries 4–7). This saturated lactone synthesis was applied for the transformation of optically active lactol 1 m derived from d-(+)-ribonic g-lactone. The reaction proceeded selectively to produce the desired lactone 5 m, while the reaction became very slow and did not reach completion even after stirring over 7 days (Scheme 4).
units and lactol (hemiacetal) 9 bearing one N-oxyphthalimide moiety in 15 % and 13 % yields, respectively.[9] We thus wondered if acetals 8 and 9 are the key intermediates in the main stream of the present catalytic cycle for the formation of phthalide 7. Thus, 8 and 9 were subjected to the present Cu-catalyzed aerobic reaction conditions (Scheme 6).
Scheme 6. Conversion of 8 and 9 under the present reaction conditions.
Our results showed that both of the reactions provided phthalide 7, while longer reaction times were required especially for the reaction of 9 a and the yields were moderate (42 % and 51 % yields, respectively). These experimental results implied that N-oxyphthalimide installed acetals 8 and 9 are not likely the key intermediates for the present C C bond cleavage, but the side-products formed during the course of the major catalytic pathway. When the reaction of 6 was conducted in the presence of benzene (Scheme 7), N-phenylphthalimide (10) was isolated in 15 % yield along with the formation of phthalide 7 as well as phthalimide (3). Compound 10 was formed presumably by addition of the phthalimide radical to benzene. Thus, the free radical mechanism is likely operating for the present C C bond cleavage event. Taking these observations into consideration, proposed reaction pathways for lactone formation through C C bond fission are described in Scheme 8. These pathways are categorized into the formation of a,b-unsaturated lactones 2 (Scheme 8 b) and a,b-saturated lactones 5 (Scheme 8 c). It is known that NHPI could be oxidized under Cu-catalyzed aerobic reaction conditions to generate the corresponding O-radical (the PINO
Scheme 4. Synthesis of lactone 5 m.
To gain mechanistic insights into the reaction, especially on the C C bond fission process, the reactions of benzoannulated lactol 6 were examined under the present reaction conditions. Indeed, 3,3-dimethyl phthalide 7 was formed in good yields (Scheme 5 a) and monitoring of the reaction progress by 1 H NMR spectroscopy revealed that lactol 6 was consumed quickly within 10–15 min along with generation of several derivatives (see the Supporting Information for more details). To isolate these derivatives, we stopped the reaction of 6 after 10 min (Scheme 5 b). In addition to phthalide 7 and phthalimide (3), we could isolate acetal 8 with two N-oxy-phthalimide
Scheme 5. Reactions of benzoannulated lactol 6. Chem. Asian J. 2014, 00, 0 – 0
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Scheme 7. The reaction of 6 in the presence of benzene.
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Communication a-oxy radical I (Scheme 8 c). The same transformation including dioxygenation and radical fragmentation takes place, resulting in formation of saturated lactone 5 a as a major product. These proposed reaction mechanisms including enol ethers as one of the key intermediates could be further supported by the reaction of methyl enol ether 11 under the present reaction conditions (Scheme 9). The reaction proceeded very rapid-
Scheme 9. Reaction of enol ether 11.
ly (within 15 min) to give methyl ester 12 in 49 % yield through the C C bond cleavage along with acetal 13 in 15 % yield.[17] In summary, we have described an unprecedented aerobic Cu-catalyzed NHPI-mediated synthesis of g-butyrolactones (mainly butenolides) from the corresponding hemiacetals through radical-mediated C C bond cleavage. The g-butyrolactone skeleton is prevalent in biologically active natural products[18] and thus a variety of construction methods of these scaffolds have been developed mainly by transition-metal mediated cyclization/cyclo-addition reactions.[19, 20] The present method associated with inert C C bond cleavage of readily available cyclic hemiacetals offers a new retrosynthetic analysis for construction of g-butyrolactone structures. Further investigation on application of this radical strategy for more practical C C bond cleavage and other types of molecular transformation is now under way in our laboratory.
Scheme 8. Proposed mechanistic rationales for the reactions. See Table 2 for nature of the R group.
radical) (Scheme 8 a).[10, 11] Concerning the formation of a,b-unsaturated lactones 2, a,b-unsaturation likely takes place prior to the C C bond fission. Thus, lactol 1 a first undergoes dehydration to give endo-cyclic enol ether A (that is thermodynamically more stable than the corresponding exo-cyclic enol ether; Scheme 8 b). Abstraction of the H-radical at the allylic positon by the PINO radical[12] results in alkene migration to form aoxy radical B that is subsequently oxidized to carbocation C under the present reaction conditions. Deprotonation of C forms exo-cyclic alkene D, which is trapped with the PINO radical, resulting in installation of the N-oxy-phthalimide moiety and regeneration of a-oxy radical E. Dioxygenation of the aoxy radical E with molecular O2 gives peroxy radical F, the Fenton-like reduction[13] of which generates O-radical G. Finally, b-radical fragmentation[14, 15] of O-radical G induces subsequent C C and O N bond cleavage to form a,b-unsaturated lactone 2 a, formaldehyde, and phthalimidoyl radical (that abstracts a hydrogen radical forming phthalimide (3)).[16] In the reactions of alkoxymethyl lactols 1 ad–1 af (Table 2, entries 4–7), the first dehydration selectively generates exocyclic enol ether H, which is trapped by PINO radical to form &
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Experimental Section Synthesis of 5,5-diphenylfuran-2(5 H)-one (2 a) (Table 1, entry 8). For further procedures, see the Supporting Information. Typical Procedure: Lactol 1 a (0.127 g, 0.50 mmol), N-hydroxyphthalimide (81.5 mg, 0.5 mmol, 1.0 equiv) and CuCl (5.1 mg, 0.05 mmol, 0.1 equiv), were added to a 25 mL Schlenk tube, and back filled with oxygen before addition of solvent MeCN (5.0 mL). The reaction mixture was stirred at 80 8C under an oxygen atmosphere (1 atm) for 12 h. After the complete consumption of lactol 1 a, as judged by thin layer chromatography anyalysis, the reaction was cooled to room temperatures before quenching with pH 9 aq. ammonium buffer and the organic materials were extracted with ethyl acetate three times. The combined extracts were washed twice with water and once with brine, and dried over MgSO4. Volatile materials were removed in vacuo and the resulting crude material was subjected to flash column chromatography (hexane/ethyl
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Communication acetate = 80:20) to afford 5,5-diphenylfuran-2(5 H)-one (85.0 mg, 0.36 mmol) in 72 % yield as a white solid.
(2 a)
[10] For reviews on the use of NHPI with metal co-catalyst, see: a) F. Recupero, C. Punta, Chem. Rev. 2007, 107, 3800; b) R. A. Sheldon, I. W. C. E. Arends, J. Mol. Catal. A 2006, 251, 200; c) R. A. Sheldon, I. W. C. E. Arends, Adv. Synth. Catal. 2004, 346, 1051; d) F. Minisci, F. Recupero, G. F. Pedulli, M. Lucarini, J. Mol. Catal. A 2003, 204 – 205, 63. [11] Recent examples using Cu–NHPI systems: a) L. Chen, R. Tang, Z. Li, S. Liang, Bull. Korean Chem. Soc. 2012, 33, 459; b) C. A. Correia, C.-J. Li, Tetrahedron Lett. 2010, 51, 1172; c) W.-J. Yoo, C. A. Correia, Y. Zhang, C.-J. Li, Synlett 2009, 138; d) M. Nechab, C. Einhorn, J. Einhorn, Chem. Commun. 2004, 1500. [12] For alyllic H-abstraction by PINO radical, see: a) S. Coseri, G. D. Mendenhall, K. U. Ingold, J. Org. Chem. 2005, 70, 4629; b) Y. Ishii, T. Iwahama, S. Sukaguchi, K. Nakayama, Y. Nishiyama, J. Org. Chem. 1996, 61, 4520; c) Y. Ishii, K. Nakayama, M. Takeno, S. Sukaguchi, T. Iwahama, Y. Nishiyama, J. Org. Chem. 1995, 60, 3934. [13] For a recent report on the Fenton mechanism, see: S. RachmilovichCalis, A. Masarwa, N. Meyerstein, D. Myerstein, R. van Eldik, Chem. Eur. J. 2009, 15, 8303. [14] For reviews on b-radical fragmentation of alkoxyl radicals, see: a) J. Hartung, T. Gottwald, K. Sˇpehar, Synthesis 2002, 1469 – 1498; b) E. Suarez, M. S. Rodriguez in Radicals in Organic Chemistry, (Eds.: P. Renaud, M. P. Sibi), 2001, Wiley-VCH, Weinheim, pp. 440. [15] Baran et al recently reported generation of imidyl radical using radical fragmentation for C H imidation of heteroarenes, see: K. Foo, E. Sella, I. Thom, M. D. Eastgate, P. S. Baran, J. Am. Chem. Soc. 2014, 136, 5279. [16] 18O-labelling experiments of 1 a, 6, and 11 under an 18O2 atmosphere delivered the corresponding lactones 2 a and 7 as well as ester 12 with incorporation of an 18O atom. These results could support the proposed reaction mechanism involving peroxy radicals such as F and J as the reaction intermediate. See the Supporting Information for more details. [17] Jiao recently reported oxygenative cleavage of aryl alkenes catalyzed by NHPI under an O2 atmosphere, see: R. Lin, F. Chen, N. Jiao, Org. Lett. 2012, 14, 4158. [18] For reviews, see: a) R. A. Pilli, G. B. Rosso, M. C. F. de Oliveira, Nat. Prod. Rep. 2010, 27, 1908; b) F. Q. Alali, X.-X. Liu, J. L. McLaughlin, J. Nat. Prod. 1999, 62, 504. [19] For reviews, see: a) A. Bartoli, F. Rodier, L. Commeiras, J.-L. Parrain, G. Chouraqui, Nat. Prod. Rep. 2011, 28, 763; b) P. Langer, Synlett 2006, 3369; c) S. Ma, Acc. Chem. Res. 2003, 36, 701; d) I. Collins, J. Chem. Soc. Perkin Trans. 1 1998, 1869. [20] For recent reports for synthesis of g-butyrolactones, see: a) E. L. McInturff, J. Mowat, A. R. Waldeck, M. J. Krische, J. Am. Chem. Soc. 2013, 135, 17230; b) M. Egi, Y. Ota, Y. Nishimura, K. Shimizu, K. Azechi, S. Akai, Org. Lett. 2013, 15, 4150; c) P. A. Evans, P. A. Inglesby, K. Kilbride, Org. Lett. 2013, 15, 1798; d) S. Li, B. Miao, W. Yuan, S. Ma, Org. Lett. 2013, 15, 977; e) M. S. Reddy, Y. K. Kumar, N. Thirupathi, Org. Lett. 2012, 14, 824; f) L. huang, H. Jiang, C. Qi, X. Liu, J. Am. Chem. Soc. 2010, 132, 17652; g) K. Matsuo, M. Shindo, Org. Lett. 2010, 12, 5346; h) U. Albrecht, P. Langer, Tetrahedron 2007, 63, 4648; i) M. Alfonsi, A. Arcadi, M. Chiarini, F. Marinelli, J. Org. Chem. 2007, 72, 9510; j) Y. Liu, F. Song, S. Guo, J. Am. Chem. Soc. 2006, 128, 11332; k) C. Fu, S. Ma, Eur. J. Org. Chem. 2005, 3942; l) S. Ma, Z. Yu, Angew. Chem. Int. Ed. 2002, 41, 1775; Angew. Chem. 2002, 114, 1853.
Acknowledgements This work was supported by funding from Nanyang Technological University and Singapore Ministry of Education (Academic Research Fund Tier 2: MOE2012-T2-1-014). We thank Dr. Yongxin Li and Dr. Rakesh Ganguly (Division of Chemistry and Biological Chemistry, Nanyang Technological University) for assistance in X-ray crystallographic analysis. Keywords: C C bond cleavage · copper · homogeneous catalysis · lactones · radicals [1] For reviews, see: a) F. Chen, T. Wang, N. Jiao, Chem. Rev. 2014, 114, 8613; b) T. Seiser, T. Saget, D. N. Tran, N. Cramer, Angew. Chem. Int. Ed. 2011, 50, 7740; Angew. Chem. 2011, 123, 7884; c) N. Cramer, T. Seiser, Synlett 2011, 449; d) C. Aı¨ssa, Synthesis 2011, 3389; e) M. Murakami, T. Matsuda, Chem. Commun. 2011, 47, 1100; f) M. Rubin, M. Rubina, V. Gevorgyan, Chem. Rev. 2007, 107, 3117; g) T. Satoh, M. Miura, Top. Organomet. Chem. 2005, 14, 1; h) C.-H. Jun, Chem. Soc. Rev. 2004, 33, 610; i) B. Rybtchinski, D. Milstein, Angew. Chem. Int. Ed. 1999, 38, 870; Angew. Chem. 1999, 111, 918; j) M. Murakami, Y. Ito, In Activation of Unreactive Bonds and Organic Synthesis (Ed.: S. Murai), Springer, New York, 1999, pp. 97 – 129. [2] For an account, see: S. Chiba, Bull. Chem. Soc. Jpn. 2013, 86, 1400. [3] a) Y.-F. Wang, H. Chen, X. Zhu, S. Chiba, J. Am. Chem. Soc. 2012, 134, 11980; b) L. Zhang, G. Y. Ang, S. Chiba, Org. Lett. 2011, 13, 1622. [4] P. C. Too, Y. L. Tnay, S. Chiba, Beilstein J. Org. Chem. 2013, 9, 1217. [5] For a review on aliphatic C H oxidation with O- and N-radicals, see: S. Chiba, H. Chen, Org. Biomol. Chem. 2014, 12, 4051. [6] Lactols 1 exist as an equilibrium mixture with the corresponding acylic forms, g-hydroxy ketones. See the Supporting Information for more details. [7] Formation of phthalimide (3) was observed in all the reactions with NHPI. Phthalimide (3) is easily solidified with poor solubility towards organic solvents so that it is easily lost during the work-up process. Therefore, we did not pursue to elucidate the yield of phthalimide (3) in the other cases. [8] For example, the reaction of hemiacetal 1 n (that is in equilibrium with its acyclic form) under the present reaction conditions gave 1,4-diketone 1 n’ as a sole product. For the report on oxidation of secondary benzylic alcohols under the Cu – NHPI system, see: G. Yang, L. Wang, J. Li, Y. Zhang, X. D. Ying, S. Gao, Res. Chem. Intermed. 2012, 38, 775.
Received: October 17, 2014 Revised: November 3, 2014 Published online on && &&, 0000
[9] The structure of acetal 8 was secured by X-ray crystallographic analysis. See the Supporting Information for the proposed mechanism for the formation of acetals 8 and 9.
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Communication
COMMUNICATION & Copper Catalysis
Let’s get physical: A Cu-catalyzed aerobic C C bond cleavage of cyclic hemiacetals (lactols) into lactones was achieved in the presence of N-hydroxy phthalimide (NHPI). This reaction is composed of a multistep sequence including a) formation of exo-cyclic enol ethers through dehydration; b) addition of phthalimide N-oxyl radical to the enol ethers followed by trap of the resulting C-radicals with molecular oxygen to form peroxy radicals; c) reductive generation of oxy radicals and subsequent b-radical fragmentation to generate lactones.
Ya Lin Tnay, Shunsuke Chiba* && – && Copper-Catalyzed Aerobic C C Bond Cleavage of Lactols with N-Hydroxy Phthalimide for Synthesis of Lactones
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Communication
Copper Catalysis
Copper-Catalyzed Aerobic C C Bond Cleavage of Lactols with NHydroxy Phthalimide for Synthesis of Lactones Ya Lin Tnay and Shunsuke Chiba*[a] Abstract: The transformation of cyclic hemiacetals (lactols) into lactones has been achieved by Cu-catalyzed aerobic C C bond cleavage in the presence of N-hydroxy phthalimide (NHPI). The present process is composed of a multistep sequence including a) formation of exo-cyclic enol ethers by dehydration; b) addition of phthalimide N-oxyl radical to the enol ethers followed by trapping of the resulting C-radicals with molecular oxygen to form peroxy radicals; c) reductive generation of oxy radicals and subsequent b-radical fragmentation to generate lactones.
Molecular transformations involving fission of inert C C bonds provide new methods for the synthetic design of the target molecules. Therefore, a variety of methods realizing efficient C C bond cleavage and functionalization have been exploited, in which catalytic processes using transition metals [M] are a recent main trend in the method development.[1] These reactions are commonly driven by release of ring strain, diminution of steric congestion, or generation of a relatively stable C [M] bond as the driving force of the inert C C bond cleavage. Our group has been working on the development of aliphatic C H oxidation using hetero-atom radicals generated under Cu-catalyzed aerobic reaction conditions.[2, 3] In this context, we recently disclosed a Cu-catalyzed aerobic oxygenation of aliphatic C H bonds through 1,5-H radical transfer of the oxygen-centered radical generated from peroxy derivatives (Scheme 1).[4, 5] For example, the reaction of alkane 1,1-diphenylpentane under Cu-catalyzed aerobic reaction conditions in the presence of N-hydroxyphthalimide (NHPI) delivered lactol 1 a in 41 % yield after 24 h. This alkane oxygenation takes place through a step-wise radical sequence involving 1) phthalimide N-oxyl radical-mediated intermolecular benzylic C H oxygenation with molecular oxygen (at the carbon marked in green); 2) generation of oxygen-centered radical and its 1,5-H radical abstraction (at the carbon marked in red) followed by aerobic oxygenation (Scheme 1). During the course of this
Scheme 1. Preliminary finding for the formation of lactone 2 a by oxidative C C bond cleavage from 1 a.
study, it was surprisingly found that prolonging the reaction time to 36 h gave rise to another product, namely, a,b-unsaturated lactone 2 a in 19 % yield along 1 a in 26 % yield. It was assumed that a,b-unsaturated lactone 2 a was formed from lactol 1 a through an unstrained C Me bond cleavage as well as a,b-unsaturation under the present reaction conditions. We therefore became interested in this unprecedented molecular transformation and aimed at developing a new chemical transformation of lactols to the corresponding lactones by the C C bond fission. Optimization of the reaction conditions and scope of the reaction as well as the detailed reaction mechanism are described herein. We began our investigation using lactol 1 a[6] to optimize the reaction conditions for the synthesis of lactone 2 a (Table 1). It was found that the presence of Cu-catalysts, NHPI, and molecular O2 was essential for the reaction to occur. Indeed, treatment of lactol 1 a with CuCl (20 mol %) and NHPI A (1 equiv) in MeCN under an O2 atmosphere at 50 8C provided a,b-unsaturated lactone 2 a in 49 % yield (Table 1, entry 1). Raising the reaction temperature to 80 8C improved the yield of 2 a to 71 % yield (Table 1, entry 2). Screening the Cu salts and solvents revealed that the reaction performs best with CuCl in
[a] Y. L. Tnay, Prof. S. Chiba Division of Chemistry and Biological Chemistry School of Physical and Mathematical Sciences Nanyang Technological University Singapore 637371 (Singapore) E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/asia.201403196. Chem. Asian J. 2014, 00, 0 – 0
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Communication Table 1. Optimization of the reaction conditions.[a]
Entry
[Cu] (mol %)
Additive [equiv]
Solvent
T [8C]
t [h]
Yield [%]
1 2 3 4 5 6 7 8[b] 9 10 11 12
CuCl (20) CuCl (20) CuBr (20) CuI (20) Cu(OAc)2 (20) CuCl (20) CuCl (20) CuCl (10) CuCl (5) CuCl (20) CuCl (20) CuCl (20)
A (1) A (1) A (1) A (1) A (1) A (1) A (1) A (1) A (1) B (1) C (1) D (1)
MeCN MeCN MeCN MeCN MeCN EtOAc DMSO MeCN MeCN MeCN MeCN MeCN
50 80 80 80 80 80 80 80 80 80 80 80
7 6 19 19 19 20 24 12 24 48 48 24
49 71 50 11 11 55 64 72 72 45 13 0
Scheme 2. Synthetic scope of a,b-unsaturated-g-butyrolactones 2. [a] Lactols 1 except for 1 k exist as an equilibrium mixture with their acyclic forms, ghydroxy ketones (see the Supporting Information for more details).
[a] The reactions were carried out using 0.5 mmol of 1 a in 5 mL of solvent (0.1 m) under an O2 atmosphere (1 atm). Lactol 1 a exists as an equilibrium mixture with its acyclic form, g-hydroxy ketone (see the Supporting Information for more details). [b] Phthalimide (3) was isolated in 20 % yield.
Scheme 3. The reaction of d-hydroxy ketone 1 l.
product, which is likely formed through dehydration followed by subsequent allylic oxygenation. The effect of the hemiacetal substituent R4 was then examined (Table 2). Changing the methyl group (1 a) to ethyl (1 aa) and isopropyl (1 ab) lowered the mass-balance of the products (Table 2, entries 1 and 2), but intriguingly delivered not only a,b-unsaturated lactone 2 a but also a,b-saturated lactone (gbutyrolactone) 5 a in the ratio of about 2:1. The reaction with
MeCN (Table 1, entries 3–7). The catalyst loading of CuCl could be lowered to 5 mol % while maintaining the yield of 2 a, albeit with a longer reaction time (Table 1, entries 8 and 9). It is noteworthy that in the reaction using 10 mol % CuCl and one equivalent of NHPI, phthalimide (3) was isolated in 20 % yield (Table 1, entry 8).[7] The effect of additives was next examined. Use of N-hydroxysuccinimide B or N-hydroxybenzotriazole C, instead of NHPI A, was not optimal for the present transformation (Table 1, entries 10 and 11). Lactone 2 a was not formed in the reaction with TEMPO D (Table 1, entry 12). Having optimized the reaction conditions (Table 1, entry 8 with 10 mol % of CuCl), we next investigated the substrate scope of hemiacetals 1 (Scheme 2). It was found that the g-position should be fully substituted (R1 and R2) to enable the present catalytic C C bond fission and a,b-unsaturation for the synthesis of lactone 2.[8] Various aryl groups including a thienyl moiety could be installed at the g-position to afford the corresponding lactone 2 in good to moderate yields. The reactions of g-dialkyl lactols 1 i and 1 j also proceeded to afford the corresponding a,b-unsaturated lactones 2 i and 2 j in acceptable yields, respectively. Installation of a methyl group at the b-position (R3) did not disturb the process, thereby affording lactone 2 k in 62 % yield. The reaction of d-hydroxy ketone 1 l (that is observed as a sole acyclic form without 6-membered ring hemiacetal) under the present reaction conditions delivered the desired a,b-unsaturated lactone 2 l in only 22 % yield (Scheme 3). In this case, 1,3-diketone 4 l was isolated in 23 % yield as a major &
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Table 2. Effect of hemiacetal substituent for the formation of lactones 2 a and 5 a.[a]
Entry 1 2 3[b] 4 5 6 7
1 (R4) 4
1 aa (R = Et) 1 ab (R4 = iPr) 1 ac (R4 = Ph) 1 ad (R4 = CH2OBn) 1 ae (R4 = CH2OMe) 1 ae (R4 = CH2OMe) 1 af (R4 = CH2OTBS)
T [8C]
t [h]
2 a [%]
5 a [%]
80 80 80 80 80 50 50
7 3 8 48 24 72 168
25 24 0 20 8 5 1
13 10 0 60 52 70 61
[a] The reactions were carried out using 0.5 mmol of 1 a in 5 mL of solvent (0.1 m) under an O2 atmosphere (1 atm). Lactols 1 (except for 1 ac) exist as an equilibrium mixture with their acyclic forms, g-hydroxy ketones (see the Supporting Information for more details). [b] 1 ac is observed as a sole acyclic form without its lactol form (see the Supporting Information for more details).
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Communication lactol 1 ac with a phenyl group was unsuccessful (Table 2, entry 3). It is noteworthy that the reactions with lactols 1 ad– 1 af bearing alkoxymethyl functions as R4 delivered saturated g-butyrolactone 5 a as a major product despite longer reaction times (Table 2, entries 4–7). This saturated lactone synthesis was applied for the transformation of optically active lactol 1 m derived from d-(+)-ribonic g-lactone. The reaction proceeded selectively to produce the desired lactone 5 m, while the reaction became very slow and did not reach completion even after stirring over 7 days (Scheme 4).
units and lactol (hemiacetal) 9 bearing one N-oxyphthalimide moiety in 15 % and 13 % yields, respectively.[9] We thus wondered if acetals 8 and 9 are the key intermediates in the main stream of the present catalytic cycle for the formation of phthalide 7. Thus, 8 and 9 were subjected to the present Cu-catalyzed aerobic reaction conditions (Scheme 6).
Scheme 6. Conversion of 8 and 9 under the present reaction conditions.
Our results showed that both of the reactions provided phthalide 7, while longer reaction times were required especially for the reaction of 9 a and the yields were moderate (42 % and 51 % yields, respectively). These experimental results implied that N-oxyphthalimide installed acetals 8 and 9 are not likely the key intermediates for the present C C bond cleavage, but the side-products formed during the course of the major catalytic pathway. When the reaction of 6 was conducted in the presence of benzene (Scheme 7), N-phenylphthalimide (10) was isolated in 15 % yield along with the formation of phthalide 7 as well as phthalimide (3). Compound 10 was formed presumably by addition of the phthalimide radical to benzene. Thus, the free radical mechanism is likely operating for the present C C bond cleavage event. Taking these observations into consideration, proposed reaction pathways for lactone formation through C C bond fission are described in Scheme 8. These pathways are categorized into the formation of a,b-unsaturated lactones 2 (Scheme 8 b) and a,b-saturated lactones 5 (Scheme 8 c). It is known that NHPI could be oxidized under Cu-catalyzed aerobic reaction conditions to generate the corresponding O-radical (the PINO
Scheme 4. Synthesis of lactone 5 m.
To gain mechanistic insights into the reaction, especially on the C C bond fission process, the reactions of benzoannulated lactol 6 were examined under the present reaction conditions. Indeed, 3,3-dimethyl phthalide 7 was formed in good yields (Scheme 5 a) and monitoring of the reaction progress by 1 H NMR spectroscopy revealed that lactol 6 was consumed quickly within 10–15 min along with generation of several derivatives (see the Supporting Information for more details). To isolate these derivatives, we stopped the reaction of 6 after 10 min (Scheme 5 b). In addition to phthalide 7 and phthalimide (3), we could isolate acetal 8 with two N-oxy-phthalimide
Scheme 5. Reactions of benzoannulated lactol 6. Chem. Asian J. 2014, 00, 0 – 0
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Scheme 7. The reaction of 6 in the presence of benzene.
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Communication a-oxy radical I (Scheme 8 c). The same transformation including dioxygenation and radical fragmentation takes place, resulting in formation of saturated lactone 5 a as a major product. These proposed reaction mechanisms including enol ethers as one of the key intermediates could be further supported by the reaction of methyl enol ether 11 under the present reaction conditions (Scheme 9). The reaction proceeded very rapid-
Scheme 9. Reaction of enol ether 11.
ly (within 15 min) to give methyl ester 12 in 49 % yield through the C C bond cleavage along with acetal 13 in 15 % yield.[17] In summary, we have described an unprecedented aerobic Cu-catalyzed NHPI-mediated synthesis of g-butyrolactones (mainly butenolides) from the corresponding hemiacetals through radical-mediated C C bond cleavage. The g-butyrolactone skeleton is prevalent in biologically active natural products[18] and thus a variety of construction methods of these scaffolds have been developed mainly by transition-metal mediated cyclization/cyclo-addition reactions.[19, 20] The present method associated with inert C C bond cleavage of readily available cyclic hemiacetals offers a new retrosynthetic analysis for construction of g-butyrolactone structures. Further investigation on application of this radical strategy for more practical C C bond cleavage and other types of molecular transformation is now under way in our laboratory.
Scheme 8. Proposed mechanistic rationales for the reactions. See Table 2 for nature of the R group.
radical) (Scheme 8 a).[10, 11] Concerning the formation of a,b-unsaturated lactones 2, a,b-unsaturation likely takes place prior to the C C bond fission. Thus, lactol 1 a first undergoes dehydration to give endo-cyclic enol ether A (that is thermodynamically more stable than the corresponding exo-cyclic enol ether; Scheme 8 b). Abstraction of the H-radical at the allylic positon by the PINO radical[12] results in alkene migration to form aoxy radical B that is subsequently oxidized to carbocation C under the present reaction conditions. Deprotonation of C forms exo-cyclic alkene D, which is trapped with the PINO radical, resulting in installation of the N-oxy-phthalimide moiety and regeneration of a-oxy radical E. Dioxygenation of the aoxy radical E with molecular O2 gives peroxy radical F, the Fenton-like reduction[13] of which generates O-radical G. Finally, b-radical fragmentation[14, 15] of O-radical G induces subsequent C C and O N bond cleavage to form a,b-unsaturated lactone 2 a, formaldehyde, and phthalimidoyl radical (that abstracts a hydrogen radical forming phthalimide (3)).[16] In the reactions of alkoxymethyl lactols 1 ad–1 af (Table 2, entries 4–7), the first dehydration selectively generates exocyclic enol ether H, which is trapped by PINO radical to form &
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Experimental Section Synthesis of 5,5-diphenylfuran-2(5 H)-one (2 a) (Table 1, entry 8). For further procedures, see the Supporting Information. Typical Procedure: Lactol 1 a (0.127 g, 0.50 mmol), N-hydroxyphthalimide (81.5 mg, 0.5 mmol, 1.0 equiv) and CuCl (5.1 mg, 0.05 mmol, 0.1 equiv), were added to a 25 mL Schlenk tube, and back filled with oxygen before addition of solvent MeCN (5.0 mL). The reaction mixture was stirred at 80 8C under an oxygen atmosphere (1 atm) for 12 h. After the complete consumption of lactol 1 a, as judged by thin layer chromatography anyalysis, the reaction was cooled to room temperatures before quenching with pH 9 aq. ammonium buffer and the organic materials were extracted with ethyl acetate three times. The combined extracts were washed twice with water and once with brine, and dried over MgSO4. Volatile materials were removed in vacuo and the resulting crude material was subjected to flash column chromatography (hexane/ethyl
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Communication acetate = 80:20) to afford 5,5-diphenylfuran-2(5 H)-one (85.0 mg, 0.36 mmol) in 72 % yield as a white solid.
(2 a)
[10] For reviews on the use of NHPI with metal co-catalyst, see: a) F. Recupero, C. Punta, Chem. Rev. 2007, 107, 3800; b) R. A. Sheldon, I. W. C. E. Arends, J. Mol. Catal. A 2006, 251, 200; c) R. A. Sheldon, I. W. C. E. Arends, Adv. Synth. Catal. 2004, 346, 1051; d) F. Minisci, F. Recupero, G. F. Pedulli, M. Lucarini, J. Mol. Catal. A 2003, 204 – 205, 63. [11] Recent examples using Cu–NHPI systems: a) L. Chen, R. Tang, Z. Li, S. Liang, Bull. Korean Chem. Soc. 2012, 33, 459; b) C. A. Correia, C.-J. Li, Tetrahedron Lett. 2010, 51, 1172; c) W.-J. Yoo, C. A. Correia, Y. Zhang, C.-J. Li, Synlett 2009, 138; d) M. Nechab, C. Einhorn, J. Einhorn, Chem. Commun. 2004, 1500. [12] For alyllic H-abstraction by PINO radical, see: a) S. Coseri, G. D. Mendenhall, K. U. Ingold, J. Org. Chem. 2005, 70, 4629; b) Y. Ishii, T. Iwahama, S. Sukaguchi, K. Nakayama, Y. Nishiyama, J. Org. Chem. 1996, 61, 4520; c) Y. Ishii, K. Nakayama, M. Takeno, S. Sukaguchi, T. Iwahama, Y. Nishiyama, J. Org. Chem. 1995, 60, 3934. [13] For a recent report on the Fenton mechanism, see: S. RachmilovichCalis, A. Masarwa, N. Meyerstein, D. Myerstein, R. van Eldik, Chem. Eur. J. 2009, 15, 8303. [14] For reviews on b-radical fragmentation of alkoxyl radicals, see: a) J. Hartung, T. Gottwald, K. Sˇpehar, Synthesis 2002, 1469 – 1498; b) E. Suarez, M. S. Rodriguez in Radicals in Organic Chemistry, (Eds.: P. Renaud, M. P. Sibi), 2001, Wiley-VCH, Weinheim, pp. 440. [15] Baran et al recently reported generation of imidyl radical using radical fragmentation for C H imidation of heteroarenes, see: K. Foo, E. Sella, I. Thom, M. D. Eastgate, P. S. Baran, J. Am. Chem. Soc. 2014, 136, 5279. [16] 18O-labelling experiments of 1 a, 6, and 11 under an 18O2 atmosphere delivered the corresponding lactones 2 a and 7 as well as ester 12 with incorporation of an 18O atom. These results could support the proposed reaction mechanism involving peroxy radicals such as F and J as the reaction intermediate. See the Supporting Information for more details. [17] Jiao recently reported oxygenative cleavage of aryl alkenes catalyzed by NHPI under an O2 atmosphere, see: R. Lin, F. Chen, N. Jiao, Org. Lett. 2012, 14, 4158. [18] For reviews, see: a) R. A. Pilli, G. B. Rosso, M. C. F. de Oliveira, Nat. Prod. Rep. 2010, 27, 1908; b) F. Q. Alali, X.-X. Liu, J. L. McLaughlin, J. Nat. Prod. 1999, 62, 504. [19] For reviews, see: a) A. Bartoli, F. Rodier, L. Commeiras, J.-L. Parrain, G. Chouraqui, Nat. Prod. Rep. 2011, 28, 763; b) P. Langer, Synlett 2006, 3369; c) S. Ma, Acc. Chem. Res. 2003, 36, 701; d) I. Collins, J. Chem. Soc. Perkin Trans. 1 1998, 1869. [20] For recent reports for synthesis of g-butyrolactones, see: a) E. L. McInturff, J. Mowat, A. R. Waldeck, M. J. Krische, J. Am. Chem. Soc. 2013, 135, 17230; b) M. Egi, Y. Ota, Y. Nishimura, K. Shimizu, K. Azechi, S. Akai, Org. Lett. 2013, 15, 4150; c) P. A. Evans, P. A. Inglesby, K. Kilbride, Org. Lett. 2013, 15, 1798; d) S. Li, B. Miao, W. Yuan, S. Ma, Org. Lett. 2013, 15, 977; e) M. S. Reddy, Y. K. Kumar, N. Thirupathi, Org. Lett. 2012, 14, 824; f) L. huang, H. Jiang, C. Qi, X. Liu, J. Am. Chem. Soc. 2010, 132, 17652; g) K. Matsuo, M. Shindo, Org. Lett. 2010, 12, 5346; h) U. Albrecht, P. Langer, Tetrahedron 2007, 63, 4648; i) M. Alfonsi, A. Arcadi, M. Chiarini, F. Marinelli, J. Org. Chem. 2007, 72, 9510; j) Y. Liu, F. Song, S. Guo, J. Am. Chem. Soc. 2006, 128, 11332; k) C. Fu, S. Ma, Eur. J. Org. Chem. 2005, 3942; l) S. Ma, Z. Yu, Angew. Chem. Int. Ed. 2002, 41, 1775; Angew. Chem. 2002, 114, 1853.
Acknowledgements This work was supported by funding from Nanyang Technological University and Singapore Ministry of Education (Academic Research Fund Tier 2: MOE2012-T2-1-014). We thank Dr. Yongxin Li and Dr. Rakesh Ganguly (Division of Chemistry and Biological Chemistry, Nanyang Technological University) for assistance in X-ray crystallographic analysis. Keywords: C C bond cleavage · copper · homogeneous catalysis · lactones · radicals [1] For reviews, see: a) F. Chen, T. Wang, N. Jiao, Chem. Rev. 2014, 114, 8613; b) T. Seiser, T. Saget, D. N. Tran, N. Cramer, Angew. Chem. Int. Ed. 2011, 50, 7740; Angew. Chem. 2011, 123, 7884; c) N. Cramer, T. Seiser, Synlett 2011, 449; d) C. Aı¨ssa, Synthesis 2011, 3389; e) M. Murakami, T. Matsuda, Chem. Commun. 2011, 47, 1100; f) M. Rubin, M. Rubina, V. Gevorgyan, Chem. Rev. 2007, 107, 3117; g) T. Satoh, M. Miura, Top. Organomet. Chem. 2005, 14, 1; h) C.-H. Jun, Chem. Soc. Rev. 2004, 33, 610; i) B. Rybtchinski, D. Milstein, Angew. Chem. Int. Ed. 1999, 38, 870; Angew. Chem. 1999, 111, 918; j) M. Murakami, Y. Ito, In Activation of Unreactive Bonds and Organic Synthesis (Ed.: S. Murai), Springer, New York, 1999, pp. 97 – 129. [2] For an account, see: S. Chiba, Bull. Chem. Soc. Jpn. 2013, 86, 1400. [3] a) Y.-F. Wang, H. Chen, X. Zhu, S. Chiba, J. Am. Chem. Soc. 2012, 134, 11980; b) L. Zhang, G. Y. Ang, S. Chiba, Org. Lett. 2011, 13, 1622. [4] P. C. Too, Y. L. Tnay, S. Chiba, Beilstein J. Org. Chem. 2013, 9, 1217. [5] For a review on aliphatic C H oxidation with O- and N-radicals, see: S. Chiba, H. Chen, Org. Biomol. Chem. 2014, 12, 4051. [6] Lactols 1 exist as an equilibrium mixture with the corresponding acylic forms, g-hydroxy ketones. See the Supporting Information for more details. [7] Formation of phthalimide (3) was observed in all the reactions with NHPI. Phthalimide (3) is easily solidified with poor solubility towards organic solvents so that it is easily lost during the work-up process. Therefore, we did not pursue to elucidate the yield of phthalimide (3) in the other cases. [8] For example, the reaction of hemiacetal 1 n (that is in equilibrium with its acyclic form) under the present reaction conditions gave 1,4-diketone 1 n’ as a sole product. For the report on oxidation of secondary benzylic alcohols under the Cu – NHPI system, see: G. Yang, L. Wang, J. Li, Y. Zhang, X. D. Ying, S. Gao, Res. Chem. Intermed. 2012, 38, 775.
Received: October 17, 2014 Revised: November 3, 2014 Published online on && &&, 0000
[9] The structure of acetal 8 was secured by X-ray crystallographic analysis. See the Supporting Information for the proposed mechanism for the formation of acetals 8 and 9.
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Communication
COMMUNICATION & Copper Catalysis
Let’s get physical: A Cu-catalyzed aerobic C C bond cleavage of cyclic hemiacetals (lactols) into lactones was achieved in the presence of N-hydroxy phthalimide (NHPI). This reaction is composed of a multistep sequence including a) formation of exo-cyclic enol ethers through dehydration; b) addition of phthalimide N-oxyl radical to the enol ethers followed by trap of the resulting C-radicals with molecular oxygen to form peroxy radicals; c) reductive generation of oxy radicals and subsequent b-radical fragmentation to generate lactones.
Ya Lin Tnay, Shunsuke Chiba* && – && Copper-Catalyzed Aerobic C C Bond Cleavage of Lactols with N-Hydroxy Phthalimide for Synthesis of Lactones
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