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Cite this: Org. Biomol. Chem., 2013, 11, 6255 Received 15th July 2013, Accepted 31st July 2013 DOI: 10.1039/c3ob41455h

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N-Heterocyclic carbene-catalyzed highly enantioselective synthesis of substituted dihydropyranopyrazolones† Han-Ming Zhang, Hui Lv and Song Ye*

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Highly optically pure multisubstituted dihydropyrano[2,3-c]pyrazol6-(1H)-ones were synthesized via the N-heterocyclic carbene-catalyzed enantioselective [4 + 2] annulation of α-chloroaldehydes and pyrazolone-derived oxodienes.

Pyrazolone and its derivatives are valuable molecules occurring in many bioactive natural products and synthetic compounds.1 Dihydropyrano[2,3-c]pyrazol-6(1H)-ones, which combine two interesting heterocycles of pyranone and pyrazolone, are of synthetic and pharmaceutical interest.2 However, the enantioselective synthesis of dihydropyranopyrazolones has rarely been reported. N-Heterocyclic carbene (NHC) catalysis has received widespread attention in past decades.3 They have been successfully used for a wide variety of reactions of aldehydes and functionalized aldehydes.4 In 2004, Rovis et al. reported the pioneering NHC-catalyzed conversion of α-haloaldehydes into acylating agents.5 In 2006, Bode et al. developed the first enantioselective NHC-catalyzed cyclization of chloroaldehydes with oxodienes.6 The enantioselective NHC-catalyzed cyclization of chloroaldehydes with azadienes was developed in our group.7 We also developed a series of NHC-catalyzed [4 + 2] cyclizations of ketenes with heterodienes, such as 3-alkylenyloxindoles and o-quinone methides,8 involving re-aromatization as the major driving force for the reaction.9 In this paper, we present an NHC-catalyzed enantioselective [4 + 2] cyclization of α-chloroaldehydes with 4-arylidenylpyrazolones for the synthesis of dihydropyrano[2,3-c]pyrazol-6(1H)-ones. 4-Arylidenylpyrazolones have been used as two carbon synthons for the cyclization reactions.10 However, the [4 + 2] cycloaddition reaction of 4-arylidenylpyrazolones as four atom heterodienes remains unexplored.

Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China. E-mail: [email protected]; Fax: +86 10 6255 4449; Tel: +86 10 6264 1156 † Electronic supplementary information (ESI) available: Experimental procedures and compound characterizations (PDF). CCDC 949134 (3f ). For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c3ob41455h

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Initially, the reaction of α-chloroaldehyde 1a with 4-arylidenylpyrazolone 2a was explored under NHC catalysis (Table 1). We were happy to find that the desired [4 + 2] cycloadduct 3a was obtained in 56% yield with a 2 : 1 diastereomerical ratio and 45% ee of the major cis-diastereomer in the presence of 10 mol% chiral NHC precursor 4a,11 10 mol% Cs2CO3 and 1.5 equiv. of diisopropylethylamine (entry 1). The NHC 4b with a free hydroxy group led to improved enantioselectivity (83% ee) (entry 2). Rovis’ tetracyclic NHC 5a12 derived from 2-aminoindanol was then tested, which resulted in high yield (80%) and excellent enantioselectivity (99% ee) (entry 3). The NHC 5b with a bulky N-mesityl group, developed by Bode et al.,13 oﬀered even better yield and enantioselectivity (entry 4). The reaction went well in various solvents with varied diastereoselectivities but excellent enantioselectivity (entries 4–7). Careful examination revealed that the cycloadduct cis-3a could be epimized to trans-3a under the reaction conditions with elongated reaction time. Thus a reduced loading of base is employed for the reaction. The diastereomeric ratio was improved to 9 : 1 when Cs2CO3 was removed from the reaction and 1.4 equiv. of diisopropylethylamine was used as the base to generate the NHC in situ from its precursor and neutralize the hydrochloride generated (entry 8). Further improvement of diastereoselectivity (dr = 12 : 1) was realized when 1.2 equiv. of triethylamine was used (entry 9). With the optimized reaction conditions in hand, several α-chloroaldehydes and 4-arylidenylpyrazolones were then tested (Table 2). Arylidenylpyrazolones with various substituents on phenyl groups, either electron-donating ( p-Me, MeO) or electron-withdrawing substituents ( p-F, Cl, Br, CN), proceeded smoothly to give the desired cycloadduct in high yield with good diastereoselectivity and excellent enantioselectivity (entries 2–7). The meta-substituent (m-Me, MeO, Cl) has little impact on the reaction (entries 8–10). It is necessary to note that the diastereoselectivity was switched to favor the transcycloadduct when arylidenylpyrazolones with o-chlorophenyl (2k) and 1-naphthyl (2l) were used (entries 12 and 13). Aliphatic chloroaldehydes (1b–1c) were also tested for the reaction, which worked as well as the aromatic ones, giving the

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Table 1

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Optimization of reaction conditions

Entry

Precat.a

Base (equiv.)

Solvent

Time

drb

Yieldc (%)

eed (%)

1 2 3 4 5 6 7 8 9

4a 4b 5a 5b 5b 5b 5b 5b 5b

DIEA (1.5) DIEA (1.5) DIEA (1.5) DIEA (1.5) DIEA (1.5) DIEA (1.5) DIEA (1.5) DIEA (1.4) f Et3N (1.2) f

DCM DCM DCM DCM Et2O THF Toluene DCM DCM

1.5 h 1.5 h 1.5 h 1.5 h 20 h 6h 7h 2h 2h

2:1 3:1 3:1 3:1 8:1 5:1 5:1 9:1 12 : 1

56 60 80 89 95 79 75 94 95

54e 83e 99 >99 99 99 99 99 >99

a

The NHC 4′–5′ was generated from its precursor 4–5 (10 mol%) and Cs2CO3 (10 mol%) at room temperature for 30 min, and used immediately. Determined by 1H NMR (300 MHz) of unpurified reaction mixtures. c Isolated yield of a mixture of two diastereomers. d Determined by HPLC on a chiral column. e The opposite enantiomer ent-3a was isolated as the major product. f No Cs2CO3 was added for entries 8 and 9. DIEA = diisopropylethylamine.

b

Table 2

NHC-catalyzed reaction with 4-arylidenylpyrazolones

Entry

1, R

2, Ar

3

dr

Yieldb (%)

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

1a, Ph 1a, Ph 1a, Ph 1a, Ph 1a, Ph 1a, Ph 1a, Ph 1a, Ph 1a, Ph 1a, Ph 1a, Ph 1a, Ph 1b, n-C5H11 1c, n-C9H19 1c, n-C9H19 1c, n-C9H19

2a, Ph 2b, p-MeC6H4 2c, p-MeOC6H4 2d, p-FC6H4 2e, p-ClC6H4 2f, p-BrC6H4 2g, p-CNC6H4 2h, m-MeC6H4 2i, m-MeOC6H4 2j, m-ClC6H4 2k, o-ClC6H4 2l, 1-Naphthyl 2a, Ph 2a, Ph 2b, p-MeC6H4 2d, p-ClC6H4

3a 3b 3c 3d 3e 3f 3g 3h 3i 3j 3k 3l 3m 3n 3o 3p

12 : 1 10 : 1 10 : 1 11 : 1 11 : 1 10 : 1 10 : 1 11 : 1 11 : 1 10 : 1 1:8 1 : 3 (1 : 8)d 9:1 9:1 10 : 1 9:1

95 94 90 91 89 90 87 95 90 90 83 82 85 83 84 80

a

eec (%) 99 99 98 99 99 98 91 99 99 99 99 99 99 99 99 98

Determined by 1H NMR (300 MHz) of unpurified reaction mixtures. Isolated yield. c Determined by HPLC on a chiral column. d Et3N (1.4 equiv.) and Cs2CO3 (0.1 equiv.) were used.

dihydropyranopyrazolones (3m–3p) in high yield and enantioselectivity (entries 14–17). The cis- and absolute configuration of dihydropyridinone 3f was unambiguously established by the X-ray analysis of its single crystal (Fig. 1).14 In conclusion, the NHC-catalyzed [4 + 2] annulation of α-chloroaldehydes and 4-arylidenylpyrazolones was developed. Both aromatic and aliphatic chloroaldehydes worked well to give the desired dihydropyrano[2,3-c]pyrazol-6-(1H)-ones in high yields with good diastereoselectivity and excellent enantioselectivity. Other related NHC-catalyzed annulation reactions are underway in our laboratory.

a b

6256 | Org. Biomol. Chem., 2013, 11, 6255–6257

Fig. 1 X-Ray structure of cycloadduct 3f (hydrogens, except the two at chiral carbon, are omitted for clarity).


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Acknowledgements Financial support from the National Natural Science Foundation of China (21072195) and the Ministry of Science and Technology of China (2011CB808600) is gratefully acknowledged.


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