DOI: 10.1002/chem.201303625

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& Organic Synthesis

Phosphine-Catalyzed [3+2] Cycloaddition Reactions of Azomethine Imines with Electron-Deficient Alkenes: A Facile Access to Dinitrogen-Fused Heterocycles Zhen Li, Hao Yu, Honglei Liu, Lei Zhang, Hui Jiang, Bo Wang, and Hongchao Guo*[a]

Abstract: An efficient method for the phosphine-catalyzed [3+2] cycloaddition reaction of azomethine imines with diphenylsulfonyl alkenes to give dinitrogen-fused bi- or tricyclic heterocyclic compounds in high yields has been de-

Introduction Dinitrogen-fused heterocycles are present in many pharmaceuticals, agrochemicals, biologically active compounds, and other useful chemicals. Among these compounds (Figure 1), pyrazolone derivatives are important dyes in the food, textile, photography, and cosmetics industries.[1] Phenazone is an old analgesic and antipyretic drug,[2] phenylbutazone displays antiinflammatory activity,[2] phenidone can inhibit lipoxygenase,[3] BW357U has anorectic activity.[4] Tetrahydropyrazolopyrazolones have been studied as antibacterial agents,[2] antitumor agents,[5] calcitonin agonists,[6] anti-Alzheimer agents,[7] and herbicides and pesticides.[8] Therefore, new synthetic methodologies for the synthesis of dinitrogen-fused heterocycles have attracted much attention. Among various methods, the cycloaddition reactions based on azomethine imines are practical and efficient methods, and have been extensively investigated.[9] Numerous metal-catalyzed and organocatalytic cycloadditions of azomethine imines could be employed for the synthesis of diverse dinitrogen-fused heterocycles.[10] Cu, Ni, or diarylprolinol salt-catalyzed [3+2] cycloaddition reactions of azomethine imines with alkenes[11] and gold(I)-catalyzed [3+2] cycloaddition reactions of azomethine imines with N-allenyl amides[12] afforded tetrahydropyrazolopyrazolones. Cu-catalyzed [3+2] cycloadditions of azomethine imines with alkynes provided an efficient protocol for the synthesis of dihydropyrazolopyrazolone.[13] Pd-catalyzed [3+3] cycloadditions of azomethine imines with trimethylenemethane produced hexahydropyridazine derivatives under mild conditions.[14] Pd-catalyzed [4+3] cycloadditions of azomethine imines with g-methyli-

scribed. Moreover, two phenylsulfonyl groups installed on the heterocyclic products could be conveniently removed or transformed to other functional groups, making the reaction more useful.

dene-d-valerolactones gave tetrahydropyrazolodiaze-pinones.[15] Au-catalyzed [3+3] annulation of azomethine imines with propargyl esters[16] and N-heterocyclic carbene-catalyzed stereoselective formal [3+3] cycloaddition reactions of azomethine imines with enals[17] provided tetrahydropyrazolopyridazinones. Rh-catalyzed [3+3] annulation of azomethine imines with enoldiazoacetate led to pyrazolidinone derivatives.[18] Tior Brønsted acid-catalyzed [3+2] cycloaddition reactions of azomethine imines with alkenes delivered tricyclic tetrahydroisoquinoline derivatives.[19] Ni-catalyzed [3+3] cycloaddition reactions of aromatic azomethine imines with 1,1-cyclopropane diesters gave unique tricyclic dihydroquinoline derivatives.[20] Multifunctional primary-amine-catalyzed [3+2] cycloaddition reactions of azomethine imines and cyclic enones[21] furnished tetrahydropyrazolone-fused tricyclic heterocycles. All these reactions demonstrate that the cycloaddition reactions based on azomethine imines are very useful for the synthesis of heterocyclic compounds with interesting structures. Most recently, we developed phosphine-catalyzed [3+2], [3+3], [4+3], and [3+2+3] annulation reactions of N,N’ or C,Ncyclic azomethine imines with allenoates, affording biologically important dinitrogen-fused heterocycles, such as tetrahydropyrazolopyrazolone, tetrahydropyrazolopyridazinone, tetrahydropyrazolodiazepinone, tetrahydropyrazolodiazocinone, tricyclic dihydroisoquinoline, and tetrahydroisoquinoline deriva-

[a] Z. Li, H. Yu, H. Liu, L. Zhang, H. Jiang, B. Wang, Prof. Dr. H. Guo Department of Applied Chemistry, China Agricultural University 2 West Yuanmingyuan Road, Beijing 100193 (P.R. China) Fax: (+ 86) 10-6281-5579 E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201303625. Chem. Eur. J. 2014, 20, 1731 – 1736

Figure 1. Selected examples of biologically active dinitrogen-fused heterocycles.

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Full Paper tives.[22] Inspired by this work, we conceived the possibility of introducing electron-deficient olefins to react with azomethine imines to furnish [3+2] cycloaddition reactions under phosphine catalysis conditions. Nucleophilic phosphine catalysis has emerged as an efficient tool to prepare carbo- and heterocycles.[23] Generally, in most of the phosphine-catalyzed cycloadditions, activated allenes, alkynes, Morita–Baylis–Hillman (MBH) carbonates and acetates acted as electrophiles to be attacked by phosphine to give active zwitterions, which then react with electrophilic coupling partners, leading to various annulation reactions.[23] The electron-deficient alkenes had often been used as electrophilic coupling reagents to accomplish the cycloaddition reactions,[23] and seldom employed as an electrophile to react with phosphine to form active zwitterions for conducting further annulation reactions. Herein, we report the first example of phosphine-catalyzed [3+2] cycloaddition reactions of various azomethine imines with electron-deficient phenylsulfonyl alkenes.

Results and Discussion Initial optimization experiments were conducted with N,N’cyclic azomethine imine 1 a and commercially available (Z)-1,2bis(phenylsulfonyl)ethylene (2 a) as the model substrates. Since numerous cycloadditions of azomethine imines with electrondeficient alkenes in the absence of metal catalyst or organocatalyst are known,[24] the potential background reaction from direct cycloaddition of 1 a with 2 a was first investigated. The reaction of 1 a and 2 a was carried out in 1,2-dichloroethane at 80 8C in the absence of catalyst for 48 h. TLC monitoring revealed no new spot was generated and the substrate 1 a was almost not consumed (Table 1, entry 1), therefore the background reaction at room temperature could be excluded. Then, several commercially available phosphines with different

Table 1. Optimization of reaction conditions for [3+2] cycloaddition reactions of N,N’-cyclic azomethine imines with diphenylsulfonyl alkenes.[a]

Entry

Catalyst

T [8C]

1[c] 2 3 4 5 6 7 8 9 10 11 12 13

– PPh3 Bu3P Me2PPh MePPh2 n-PrPPh2 iPrPPh2 tBuPPh2 CyPPh2 Et3N DABCO DBU DMAP

80 25 25 25 25 25 25 25 25 25 25 25 25

Yield [%][b] 0 76 72 80 84 72 74 50 67 61 72 63 35

[a] 1.5 equiv of 2 a was used. [b] Isolated yield. [c] Without catalyst and with 1,2-dichloroethane as the solvent.

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nucleophilicity were screened (entries 2–9). Using 20 mol % of PPh3, the azomethine imine 1 a was treated with 1.5 equivalents of 2 a for 48 h; delightfully, the [3+2] product 3 a could be obtained in 76 % yield (entry 2). Unfortunately, the product is a mixture of several diastereomers, which could not be separated by flash column and could also not completely be separated on several commercially available chiral columns by HPLC analysis. Moreover, the NMR spectrum of the product 3 a looks like the data of a pure compound. Therefore, the diastereomeric ratio of the cycloaddition reactions could not be determined. In Table 1, only the isolated yields of the product 3 a as a diastereomeric mixture were reported. Next, screening revealed that several other phosphines could also catalyze the cycloaddition reaction, giving the corresponding product in moderate to good yields (entries 3–9). Among these phosphines, MePPh2 gave the best yield of 84 % (entry 5). Some tertiary amines, such as Et3N, 1,4-diazobicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and 4-dimethylaminopyridine (DMAP), have also been examined for improving yields (entries 10–13). These amine catalysts could also enable the reaction to give the corresponding products, albeit in moderate yields. To achieve asymmetric cycloaddition, several commercially available chiral phosphines, such as 2,2’-bis(diphenylphosphino)-1,1’-binaphthyl (BINAP) and (+)-1,2bis[(2R,5R)-2,5-diethylphospholano]ethane (BPE), have been tried in the reaction of azomethine imine 1 a with 2 a, but the racemic product was obtained. These results have been included in the Supporting Information. With the optimized conditions established (1 (1 equiv), 2 a (1.5 equiv), MePPh2 (20 mol % in CH2Cl2)), the scope of the substrate 1 was examined (Table 2). Various N,N’-cyclic azomethine imines bearing different substituents on the benzene rings carried out the [3+2] cycloaddition, giving the tetrahydro-1H,5Hpyrazolo[1,2-a]pyrazol-1-one derivatives in 69–93 % yields (Table 2, entries 1–21). Azomethine imines bearing electron-donating groups on the benzene ring afforded excellent yields of the cycloadducts (entries 2–4). Azomethine imines bearing electron-withdrawing groups on the benzene ring also worked smoothly to provide the corresponding products in high yields (entries 5–18), but those azomethine imines with strong electron-withdrawing groups (NO2, CN, CF3) on the benzene ring resulted in slightly lower yields (entries 14–18) relative to other azomethine imines. Interestingly, for those azomethine imines with halo substituents on the benzene ring, azomethine imines containing meta-substituted benzene rings provided the corresponding cycloadducts in a somewhat lower yield than those azomethine imines bearing ortho- or para-substituted benzene rings (entries 5–13). The azomethine imines bearing 1-naphthyl, 2-naphthyl, and 2-furyl groups, were also suitable substrates, readily giving the corresponding cycloadducts in 70–84 % yields (entries 19–21). Very satisfactorily, when alkyl imine was employed, the yield of the cycloadduct reached an excellent 90 % (entry 22). Disappointingly, in most cases, the diastereomeric mixture of the products could not be separated by chiral HPLC analysis. The diastereomeric mixtures of only 3 e, 3 f, 3 p, 3 s, and 3 t were barely separated. In these cases, without exception, all diastereomeric ratios were unanimously

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Full Paper Table 2. MePPh2-catalyzed [3+2] cycloaddition reactions of azomethine imines 1 with the alkene 2 a.[a]

Entry

R

Product

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

Ph (1 a) 4-MeC6H4 (1 b) 4-OMeC6H4 (1 c) 4-iPrC6H4 (1 d) 2-FC6H4 (1 e) 3-FC6H4 (1 f) 4-FC6H4 (1 g) 2-ClC6H4 (1 h) 3-ClC6H4 (1 i) 4-ClC6H4 (1 j) 2-BrC6H4 (1 k) 3-BrC6H4 (1 l) 4-BrC6H4 (1 m) 2-NO2C6H4 (1 n) 3-NO2C6H4 (1 o) 4-NO2C6H4 (1 p) 4-CNC6H4 (1 q) 4-CF3C6H4(1 r) 1-naphthyl (1 s) 2-naphthyl (1 t) 2-furanyl (1 u) cyclohexyl (1 v)

3a 3b 3c 3d 3e 3f 3g 3h 3i 3j 3k 3l 3m 3n 3o 3p 3q 3r 3s 3t 3u 3v

Yield [%][b] 84 87 93 88 82 76 86 85 76 82 85 80 86 71 73 76 69 72 84 82 70 90

Table 3. Optimization of reaction conditions for [3+2] cycloaddition reactions of C,N-cyclic azomethine imine 4 a with (Z)-1,2-bis(phenylsulfonyl)ethylene (2 a).[a]

d.r.[c] –[d] – – – (>99:1) (98:2) – – – – – – – – – (> 99:1) – – (98:2) 93:7 – –

excellent (entries 5, 6, 16, 19, 20). The relative stereochemistry of the major diastereomer was assigned by X-ray crystallography of tetrahydropyrazolopyrazolone 3 h (Figure 2).[25] The crystals of 3 h were obtained in > 70 % yield, which indicated that the crystals were from the major diastereomer. In the crystallographic structure of 3 h, 5-aryl and 6-phenylsulfonyl are oriented homolateral in the plane; moreover, there is a strong p–p stacking between them, which allows the configuration to be more favorable. The 7-phenylsulfonyl group is oriented in the opposing direction of 5-aryl and 6-phenylsulfonyl. Next, we explored the [3+2] cycloaddition of C,N-cyclic azomethine imines 4 with (Z)-1,2-bis(phenylsulfonyl)ethylene (2 a). As shown in Table 3, the reaction conditions were first optimized with azomethine imines 4 a as the model substrate. The background reaction was first excluded by the above proce-

Yield [%][b]

1[c] 2 3 4 5 6 7 8

– Me2PPh MePPh2 PPh3 Et3N DABCO DBU DMAP

0 80 88 75 87 85 87 87

dure (Table 3, entry 1). Then, several commercially available Lewis base catalysts were evaluated. The screening results indicated that at room temperature and with dichloromethane as the solvent, all these catalysts could efficiently catalyze the cycloaddition reaction, providing the corresponding [3+2] cycloadduct in 75–88 % yield (entries 2–8). MePPh2 afforded the highest yield of 88 % (entry 3). Although the product 5 a was observed as a spot on TLC, it is a diastereomeric mixture. Unfortunately, the mixture could not be separated on several commercially available chiral columns by HPLC analysis. When using MePPh2 as the catalyst, the scope of the C,N-cyclic azomethine imines was investigated (Table 4). The reaction is tolerant to a range of azomethine imines (4 b–f), providing a series of the corresponding cycloadducts in 82–93 % yields. Electron-donating alkyl-substituted azomethine imines provided slightly higher yields than those with electron-withdrawing groups (entries 2, 3 vs. 4, 5, 6). The X-ray crystallographic structure of the major diastereomer of 5 a is shown in Figure 3.[25] Any two adjacent groups among the two phenylsulfonyl groups and benzoyl group are oriented in opposing directions.

Table 4. MePPh2-catalyzed [3+2] cycloaddition of C,N-cyclic azomethine imines 4 with (Z)-1,2-bis(phenylsulfonyl)ethylene (2 a).[a]

Entry

R

Product

1 2 3 4 5 6

H (4 a) 5-Me (4 b) 7-Me (4 c) 6-Br (4 d) 7-Br (4 e) 7-Cl (4 f)

5a 5b 5c 5d 5e 5f

Yield [%][b] 88 88 93 87 82 84

[a] 1.2 equiv of 2 a was used. [b] Isolated yield.

Figure 2. The X-ray crystallographic structure of 3 h.

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Catalyst

[a] 1.2 equiv of 2 a was used. [b] Isolated yields. [c] Without catalyst and using 1,2-dichloroethane as the solvent.

[a] 1.5 equiv of 2 a was used. [b] Isolated yield. [c] By HPLC analysis on a chiral column. [d] The diastereomeric mixtures of these products couldn’t be separated by a chiral column.

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Entry

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Figure 3. The X-ray crystallographic structure of 5 a.

We also examined the reaction of azomethine imines 1 a or 4 a with (E)-1,2-bis(phenylsulfonyl)ethylene (2 b) (Scheme 1). As expected the reactions worked efficiently to give the same products as the products from (Z)-1,2-bis(phenylsulfonyl)ethylene (2 a), namely 3 a and 5 a, respectively. This indicated that the configuration of the double bond in 2 a or 2 b has no influence on the reaction activity and stereoselectivity.

Scheme 2. MePPh2-catalyzed [3+2] cycloadditions of aromatic azomethine imines with (Z)-diphenylsulfonylethylene (2 a).

Scheme 1. MePPh2-catalyzed [3+2] cycloadditions of azomethine imines with (E)-1,2-bis(phenylsulfonyl)ethylene (2 b). Figure 4. The X-ray crystallographic structure of 7.

Besides N,N’-cyclic azomethine imines 1 and C,N-cyclic azomethine imines 4, several aromatic azomethine imines (6, 8, 10, and 12) had also been studied (Scheme 2a–d). All these azomethine imines were suitable substrates, and carried out [3+2] cycloaddition reactions to give the corresponding products (7, 9, 11, and 13) in 79–94 % yields. The X-ray crystallographic structure of the major diastereomer of 7 is shown in Figure 4.[25] Its configuration is similar to that of 5 a. Any two adjacent groups among two phenylsulfonyl groups and benzoyl group are oriented in opposing directions. Next, we examined the activity of methyl (E)-3-(phenylsulfonyl)acrylate (2 c), diethyl maleate (2 d), and dimethyl fumatate (2 e) in the [3+2] cycloaddition with azomethine imine (Scheme 3). The background reaction from direct [3+2] cycloaddition of 1 a with 2 c at room temperature was excluded according to the above-mentioned procedure. Employing 20 mol % of MePPh2 as the catalyst, the reaction proceeded at room temperature for 48 h to give the target [3+2] cycloadduct 14 in 66 % yield. In contrast, using diethyl maleate (2 d) as the substrate, its thermal cycloaddition reaction with azomethine imine 1 a could not be avoided at room temperature, leading to the corresponding product in 20 % yield, and its phosphine-catalyzed cycloaddition reaction with azomethine imine 1 a worked inefficiently, affording the cycloaddition product 15 in 36 % yield, which is the diastereomer of the thermal Chem. Eur. J. 2014, 20, 1731 – 1736

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cycloadduct. Satisfactorily, the MePPh2-catalyzed cycloaddition reaction of 2 d with C,N-cyclic imine 4 a proceeded well, giving the corresponding product 16 in 70 % yield and the thermal cycloaddition product was obtained in < 5 % yield. Very disappointedly, under the standard phosphine catalysis conditions, the thermal cycloaddition reaction of dimethyl fumatate 2 e with either 1 a or 4 a dominated the reaction process, forming

Scheme 3. MePPh2-catalyzed [3+2] cycloadditions of azomethine imines with (E)-3-(phenylsufonyl)acrylate (2 c) and diethyl maleate (2 d).

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Full Paper the thermal cycloadduct, and a little phosphine-catalyzed cycloadduct was observed on the TLC analysis. This indicated that the configuration of the double bond in 2 d and 2 e has a remarkable influence on the reaction activity, and (E)-alkene 2 e was more likely to undergo the thermal cycloaddition. The proposed mechanism for phosphine-catalyzed [3+2] cycloaddition of the azomethine imine and electron-deficient alkene is presented in Scheme 4. The zwitterion A from conjugate addition of phosphine to the alkene 2 attacks azomethine imine to give the intermediate B. Next intramolecular nucleophilic attack accomplishes the [3+2] cyclization and regenerates the catalyst forming the final [3+2] cycloaddition product.

product 3 n also underwent alcoholysis to give the derivative 20 in 89 % yield, the structure of which was unambiguously determined by the X-ray crystallographic structure (Figure 5).[25]

Figure 5. The X-ray crystallographic structure of 18.

Scheme 4. Putative mechanism of phosphine-catalyzed [3+2] cycloaddition.

The next synthetic transformations demonstrated that these products are versatile synthons (Scheme 5). Since the sulfonyl group always acts as an activating group in many synthetic methodologies, further elaboration was very easily. When the phenylsufonyl-substituted dinitrogen-fused heterocycle 3 a was treated in methanol at room temperature, the phenylsufonyl group at the 7-position of 3 a was smoothly substituted by methoxy to give the alcoholysis product 17 in 86 % yield. The

The phenylsulfonyl groups could be removed by reduction. First, the dry methanol and cleaned magnesium turnings were mixed and stirred, then 3 a was added and stirring was continued until reduction was completed, leading to reductive desulfonylation product 18 in 75 % yield. The modified Barton–Zard reaction of 3 a with ethyl isocyanoacetate in the presence of potassium tert-butoxide gave an interesting tricyclic heterocycle 19 in 70 % yield, which has never been reported before and might find potential application in bioactivity exploration. When the product 5 a was treated with magnesium in methanol at 50 8C, 5,6-dihydropyrazolo[5,1-a]isoquinoline (21), which was synthesized by an intramolecular palladium-catalyzed C H bond activation by Heo in 2010, was obtained in 78 % yield.[26] Compared with Heo’s method, this procedure is more concise. In summary, we have developed an efficient phosphine-catalyzed [3+2] cycloaddition of azomethine imines with diphenylsulfonyl alkenes with broad substrate variables, providing dinitrogen-fused heterocyclic compounds in high yields. The reaction provided a practical synthetic method for bicyclic or tricyclic heterocycles, which would be interesting in the study of bioactivities. Moreover, two phenylsulfonyl groups installed on the heterocyclic products could be conveniently removed or transformed to other functional groups, making the reaction more useful.

Experimental Section General procedure for the phosphine-catalyzed [3+2] cycloaddition reaction An oven-dried Schlenk tube (15 mL) was charged with azomethine imine (0.125 mmol), CH2Cl2 (5 mL), and 1,2-bis(phenylsulfonyl)ethylene (0.15 mmol or 0.19 mmol) at room temperature. Then, catalyst (0.025 mmol) was added to the above solution. The reaction mixture was stirred at room temperature for 48 h, and was then concentrated. The residue was purified by flash column (ethyl acetate/ petroleum ether) to afford the corresponding product.

Acknowledgements Scheme 5. Synthetic transformations of the cycloadducts. Chem. Eur. J. 2014, 20, 1731 – 1736

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This study was supported by the National Natural Science Foundation of China (no. 21172253, 21372256), the Program 1735

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Full Paper for New Century Excellent Talents in University (no. NCET-110481), the National Scientific and Technology Supporting Program of China (no. 2011BAE06B05-5), the National S&T Pillar Program of China (no. 2012BAK25B03), Research Fund for the Doctoral Program of Higher Education of China (no. 20120008110038), and the Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry and Nutrichem.

[12] [13]

[14] [15] [16]

Keywords: alkenes · azomethine cycloaddition reactions · phosphine

imine

·

catalysis

·

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Received: September 13, 2013 Revised: November 14, 2013 Published online on January 8, 2014

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