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Cite this: Chem. Commun., 2014, 50, 5710

Phosphine-catalyzed sequential annulation domino reaction: rapid construction of bicyclo[4.1.0]heptene skeletons†

Received 11th February 2014, Accepted 2nd April 2014

Jie Zheng, You Huang* and Zhengming Li

DOI: 10.1039/c4cc01097c www.rsc.org/chemcomm

A convenient and efficient phosphine-catalyzed sequential annulation domino reaction between dienic sulfones and MBH carbonates has been developed. In the presence of 20 mol% of tris(4-fluorophenyl)phosphine, functionalized bicyclo[4.1.0]heptenes were prepared in excellent yields and stereoselectivities under mild conditions.

Bicyclo[4.1.0]heptane ring systems are found in a variety of natural products and biologically active substances (Scheme 1).1–5 They are also key building blocks in organic synthesis because of their latent reactivity inherent within their structure and may participate in a wide range of ring-opening reactions.6 Among the various methods developed in the past decades for the synthesis of these useful architectures, the transitionmetal-catalyzed intramolecular cycloisomerization of heteroatom

tethered 1,6-enynes is an important and commonly employed process that contributes to atom economy concepts (Scheme 2).7 Most of the methods such as metal-catalyzed carbene transfer of diazo compounds to carbon–carbon double bonds,8 cycloisomerization of 1,6-dienes,9 ring opening of cyclopropenes,10 and the cyclopropanation of a-lithiated epoxides11 are based on the generation of metal carbenoids (Scheme 2). Gaunt and co-workers described an organocatalytic cyclopropanation reaction in which an a-chloroketone with a tethered electron deficient alkene reacts through a catalytically generated ammonium ylide followed by addition of an intramolecular conjugate to form the bicyclic structure (Scheme 2).12 Other powerful and special methods like intramolecular Simmons–Smith (IMSS) cyclopropanation are also disclosed.13,14 Although these

Scheme 1 Representative natural products and biologically active compounds containing bicyclo[4.1.0]heptane scaffolds.

State Key Laboratory and Institute of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin 300071, People’s Republic of China. E-mail: [email protected] † Electronic supplementary information (ESI) available: Experimental procedures and characterization data of new compounds and copies of NMR spectra. CCDC 972350. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4cc01097c

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Scheme 2 The construction of bicyclo[4.1.0]heptane scaffolds through an intramolecular approach and this work.

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intramolecular approaches offer important methods, there are some limitations and shortcomings of these established methods: the troublesome preparation of starting material, a specific type of product. On the other hand, the intermolecular approach is rare and would provide a more direct route to bicyclo[4.1.0]heptane with operational simplicity from simple substrates.15 Phosphine-catalyzed domino reactions have become a powerful tool in the synthesis of carbo- and heterocycles.16 In particular, MBH carbonates have been reported to be versatile C3 synthons and 1,1-dipolar synthons.17–19 Intrigued by these elegant studies, we envision that they might serve as a new kind of 1,2,3-C3 synthon. Moreover, in our continuous research into phosphine-catalyzed domino reactions, we become interested in the versatile reactivity of conjugated dienes in constructing complex skeletons.20–24 Here we report our studies on the development of an intermolecular phosphine-catalyzed reaction of 1,3-bis(sulfonyl)butadienes and MBH carbonates, which resulted in the successful synthesis of functionalized [4.1.0] bicycloalkenes. We initiated our investigation by subjecting MBH carbonate 2a to 1,3-bis(sulfonyl)butadiene 1a in the presence of Ph3P (50 mol%) in toluene at 110 1C. To our delight, 3a was isolated in 68% yield (Table 1, entry 1). We also isolated a small amount of another product the structure of which was not confirmed. The structure of 3a was unambiguously determined by X-ray diffraction analysis (see ESI†). The phosphine catalyst was proven to strongly influence the yield of 3a (entries 2–6), and tris(4-fluorophenyl)phosphine led to a better yield. Screening of other solvents such as DMSO, CHCl3 and CH3CN (entries 7–12) indicated that CHCl3 and THF delivered a comparable yield

Table 1

Optimization of the reaction conditionsa

Entry

Catalyst (mol%)

Solvent

t (1C)

Time

Yieldb (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15c 16d 17e

Ph3P (4-ClC6H4)3P (4-CH3OC6H4)3P Bu3P Me3P (4-FC6H4)3P (4-FC6H4)3P (4-FC6H4)3P (4-FC6H4)3P (4-FC6H4)3P (4-FC6H4)3P (4-FC6H4)3P (4-FC6H4)3P (4-FC6H4)3P (4-FC6H4)3P (4-FC6H4)3P (4-FC6H4)3P

Toluene Toluene Toluene Toluene Toluene Toluene DMF DMSO CHCl3 THF CH3CN EtOH CHCl3 CHCl3 CHCl3 CHCl3 CHCl3

110 110 110 110 110 110 110 110 60 60 60 60 25 40 60 60 60

45 min 48 h 1h 4.5 h 30 h 40 min 30 min 30 min 6h 6h 9h 22 h 24 h 24 h 8h 10 h 30 h

68 37 65 Complex Complex 83 Complex 44 87 83 40 28 Trace 44 86 87 86

a

Reaction conditions: 1.0 equiv. (0.3 mmol) of 1a, 2.0 equiv. (0.6 mmol) of 2a, 50 mol% of catalyst in 5 mL of solvent under Ar. b Isolated yields. c 30 mol% of (4-FC6H4)3P. d 20 mol% of (4-FC6H4)3P. e 10 mol% of (4-FC6H4)3P.

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with that of toluene (entry 6). On the other hand, lowering the temperature in CHCl3 diminished the yield sharply (entries 13 and 14). Gratifyingly, reducing the loading of the catalyst was not found to cause any loss of the yield, although the reaction became slower at fewer catalyst loading (entries 15–17). All things considered, we chose 20 mol% catalyst loading in CHCl3 at 60 1C as the optimized reaction condition (entry 16). Under the optimized conditions, a range of bicyclo[4.1.0]heptenes could be obtained efficiently from the corresponding dienic sulfones with various substituents on the aromatic ring. The results are presented in Table 2. All the products were isolated as single diastereomers. With regard to para-substituents, electronwithdrawing and -donating groups afforded products in excellent yields while the strong electron-withdrawing NO2 gave a slightly lower yield (Table 2, 3a–g). Comparison of the results indicated that the reaction efficiency was slightly affected by the position of substituents on the aryl ring (3c vs. 3h vs. 3j, 3d vs. 3i vs. 3k). Notably, 1,3-bis(sulfonyl)butadiene with biologically active fluorine-based substituents underwent the reaction cleanly (3c, 3h, and 3j). Similarly, 1l gave the corresponding product 3l in good yield (3l). More importantly, the reaction was compatible with heteroaryl frameworks, as shown in the synthesis of 3m and 3n, which furnished the desired products in satisfying yields (3m–n). For the

Table 2

Scope of the reactionsa,b

a

Reaction conditions: 1.0 equiv. (0.3 mmol) of 1, 2.0 equiv. (0.6 mmol) of 2, 20 mol% of (4-FC6H4)3P in 5 mL of CHCl3 at 60 1C for 10 h under Ar. b Isolated yields. c 12 h. d 36 h (an additional 20 mol% of catalyst and 1.0 equiv. of 2 was added to the reaction system after 24 h). e 48 h.

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2 3 4

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5 6

7 Scheme 3

Proposed mechanism.

8

1,3-bis(sulfonyl)butadienes bearing 1- and 2-naphthyl group, respectively, the corresponding products 3p and 3q were obtained in good yields (3p and 3q). Aliphatic substituted diene participated well in the reaction system (3r). It is noteworthy that the increased steric hindrance resulted in a significant decrease in efficiency (3s and 3t). Unfortunately, substituted MBH carbonate failed to give the annulation product under the optimized conditions (3u). We also prepared several a-amino acid derived thiourea-phosphine chiral catalysts17d,e to explore the asymmetric version of our sequential annulation reaction. However, no desired product was formed under the optimized conditions or at room temperature. The exploration of more effective chiral phosphines is underway. A plausible reaction mechanism is outlined in Scheme 3. The reaction was initiated by the formation of phosphorus ylide A via the commonly accepted addition–elimination–deprotonation processes. Then phosphorus ylide A underwent sterically favored g-addition to dienic sulfone 1 to give intermediate B, which underwent an intramolecular umpolung addition to generate intermediate C. Proton transfer, followed by nucleophilic substitution furnished the corresponding bicyclo[4.1.0]heptene product and regenerated the phosphine catalyst. In summary, we have disclosed a highly efficient sequential annulation of 1,3-bis(sulfonyl)butadienes and MBH carbonates catalyzed by phosphines to generate substituted bicyclo[4.1.0]heptene compounds with excellent yields and high diastereoselectivities. Aliphatic substituted dienes gave gratifying results as various aromatic substitutes. To our knowledge, they are the first example of the MBH carbonates, which serve as a new kind of 1,2,3-C3-synthon in this reaction. We expect this new process to offer chances for the development of new useful transformations and the synthesis of natural products and biologically active compounds. We thank the National Natural Science Foundation of China (21172115) and the Research Fund for the Doctoral Program of Higher Education of China (20120031110002) for financial support.

Notes and references 1 (a) C. Rieder, G. Strauss, G. Fuchs, D. Arigoni, A. Bacher and W. Eisenreich, J. Biol. Chem., 1998, 273, 18099; (b) J. Hefter,

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9

10 11

12

13 14 15

16

17

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