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Cycloaddition ofCyclohexa-2,4-dienoneswith Nitroolefins: AnUnusual Regioselectivity andExpeditious Entry into Nitro-bicyclo[2.2.2]octenonesVishwakarma Singh a , Raj Bahadur Singh a , Dilip K.Tosh a & Shaikh M. Mobin ba Department of Chemistry, Indian Institute ofTechnology , Mumbai, Indiab National Single-Crystal X-ray Diffraction Facility,Indian Institute of Technology , Mumbai, IndiaPublished online: 09 Sep 2008.

To cite this article: Vishwakarma Singh , Raj Bahadur Singh , Dilip K. Tosh & Shaikh M.Mobin (2008) Cycloaddition of Cyclohexa-2,4-dienones with Nitroolefins: An UnusualRegioselectivity and Expeditious Entry into Nitro-bicyclo[2.2.2]octenones, SyntheticCommunications: An International Journal for Rapid Communication of SyntheticOrganic Chemistry, 38:18, 3112-3120

To link to this article: http://dx.doi.org/10.1080/00397910802054263

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Cycloaddition of Cyclohexa-2,4-dienoneswith Nitroolefins: An Unusual Regioselectivity

and Expeditious Entry intoNitro-bicyclo[2.2.2]octenones

Vishwakarma Singh,1 Raj Bahadur Singh,1 Dilip K. Tosh,1 and

Shaikh M. Mobin2

1Department of Chemistry, Indian Institute of Technology, Mumbai, India2National Single-Crystal X-ray Diffraction Facility, Indian Institute of

Technology, Mumbai, India

Abstract: Cycloaddition of electron-deficient cyclohexa-2,4-dienones withnitroolefins leading to functionalized bicyclo[2.2.2]octenones with nitro groupsis reported. A highly unusual regioselectivity was observed. Crystal structure ofone of adducts has also been reported.

Keywords: Cycloaddition, Diels–Alder reaction, nitroalkene

INTRODUCTION

Cycloadditions, especially the Diels–Alder reactions, are the most versa-tile and powerful methodology for efficient synthesis of complex molecu-lar frameworks with high regio- and stereocontrol. A wide variety ofstructures have been constructed by Diels–Alder reactions of varioustypes of dienes and dienophiles.[1,2] In general, cycloaddition occursbetween an electron-rich diene (4p partner) and electron-deficient dieno-phile (2p partner), referred to as a normal Diels–Alder reaction. Alterna-tively, it may also take place between a neutral diene and dienophile, andthe third type in which an electron-deficient 4p partner participates incycloaddition with electron-rich 2p partners is known as inverse-demand

Received February 14, 2008.Address correspondence to Vishwakarma Singh, Department of Chemistry,

Indian Institute of Technology, Mumbai 400 076, India. E-mail: vks@chem.iitb.ac.in

Synthetic Communications1, 38: 3112–3120, 2008

Copyright # Taylor & Francis Group, LLC

ISSN: 0039-7911 print/1532-2432 online

DOI: 10.1080/00397910802054263

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cycloaddition. Cycloaddition of cyclohexa-2,4-dienones and their conge-ners has stimulated significant interest recently.[3] Our research group hasexplored and developed cycloaddition of cyclohexa-2,4-dienones of type1, which are electron-deficient 4p systems with electron-rich p-partners,and photochemistry of the resulting adducts has led to development ofnew methods for the synthesis of a variety of carbocyclic frameworksand natural products.[3d] Recently, it was discovered that cyclohexa-2,4-dienones of type 1, generated in situ from the readily available dimerssuch as 3, undergo cycloaddition even with electron-deficient 2p partnerssuch as ethyl acrylates.[4] In the view of the synthetic potential of bicy-clo[2.2.2]octenone[5,6] and our continuing interest in the chemistry ofcyclohexa-2,4-dienones, we further explored cycloaddition of cyclo-hexa-2,4-dienones with nitroolefins so as to devise a route to a newand rare class of bicyclo[2.2.2]octanes with nitro groups, such as 2

(Fig. 1). We wish report our results herein.Thus, the chlorohydroxy dimer 4, readily prepared from 2-

hydroxymethyl-4,6-dimethylphenol following an analogous procedure,[7]

was heated with trans-b-nitro-styrene in a sealed tube at 150 �C for 8 h.Chromatography of the reaction mixture furnished a single crystallineadduct 6 in good yield (55%) (Scheme 1). The 1H NMR (300 MHz,CDCl3) spectrum of adduct exhibited a multiplet at d 7.35–7.18 for thearomatic protons. It also showed characteristic signals at d 5.8 as amultiplet for the b-proton of b,c-enone moiety and a dd at d 5.50(J1 ¼ 6.2 Hz, J2 ¼ 2.6 Hz) for methine proton attached to the carbon-bearing nitro group. Further, it displayed signals at d 3.88 as a tripletfor the methine proton at the carbon attached to phenyl ring. Othercharacteristic signals were shown at both d 3.78 and 3.63, as a part ofan AB system (JAB ¼ 12 Hz), due to CH2Cl protons. In addition, thebridgehead proton exhibited a doublet at 3.56 (J ¼ 6.6 Hz). The splittingpattern and the coupling constants of the signals at d 5.50 and 3.56suggested the structure 6 for an adduct. However, it was difficult todistinguish between the structure 6 and its regio-isomer 7 on thebasis of spectral data alone. Hence, X-ray single-crystal structural

Figure 1. Cyclohexa-2,4-dienone, bicyclo[2.2.2]octenone, and its precursor.

Cycloaddition of Cyclohexa-2,4-dienones 3113

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determination was undertaken, which fully confirmed the structure 6 forthe adduct (Fig. 2).

The regioselectivity in the aforementioned cycloaddition appearsto highly unusual because cyclohexa-2,4-dienones generally react with

Scheme 1. Cycloaddition of nitrostyrene with cyclohexa-2,4-dienone.

Figure 2. Ortep diagram of compound 6.

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dienophiles such as acrylates and=or vinyl ketones to give the adducts oftype I (Fig. 3) with opposite regioselectivity, as a consequence of bondingbetween C-2 of the cyclohexadienone and C-1 of the dienophile bearingthe functional group.[4,8] It appears that this unusual regioselectivity isdue to the presence of the phenyl ring.

To check the generality of this cycloaddition, the dimers 8a–d wereheated with trans-b-nitrostyrene, which gave the corresponding adducts

Figure 3. General structure of adduct usually obtained during cycloaddition ofcyclohexa-2,4-dienones.

Scheme 2. Reagents and conditions: (a) o-dichlorobenzene, trans-b-nitrostyrene,sealed tube, 140–160 �C; (b) o-dichlorobenzene, p-methoxy-trans b-nitrostyrene,sealed tube, 160 �C.

Cycloaddition of Cyclohexa-2,4-dienones 3115

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10a–d in moderate to good yield (Scheme 2). It is interesting to note thatcyclohexa-2,4-dienones 5 and 8d, having methyl substituents at C2 andC4, undergo relatively efficient cycloaddition. Similar pyrolysis of thedimer 4 and 8a in the presence of p-methoxy-trans-b-nitrostyrene alsogave the adducts 11 and 12 respectively (Scheme 2). Structures of theseadducts were deduced on the basis of their spectral data and comparisonwith the spectral features of 6.

CONCLUSION

A highly unusual cycloaddition between cyclohexa-2,4-dienones withnitrostyrenes leading to functionalized bicyclo[2.2.2]octenones with nitrogroups has been described. It may be mentioned that such type of bicy-clo[2.2.2]octanes with nitro groups and functionalities in other ethanobridges are not readily accessible. Though the efficiency of the cycloaddi-tions is moderate, it is offset by rapid generation of molecular complexityin a single step.[9]

EXPERIMENTAL

3-Chloromethyl-3-hydroxy-1,5-dimethyl-8-endo-nitro-7-exo-

phenylbicyclo[2.2.2]oct-5-en-2-one (6)

A mixture of chlorohydroxydimer 4 (0.5 g, 1.3 mmol), trans-b-nitrostyrene(0.564 g, 3.8 mmol) in o-dichlorobenzene (5 mL) was heated at 150 �Cfor 4 h, after which the reaction mixture was charged on a column ofsilica gel. Elution with petroleum ether–ethyl acetate (95:5) gave someunreacted nitrostyrene. Further elution with petroleum ether–ethylacetate (90:10) gave adduct 6 (0.494 g, 55%) as a colorless solid, mp162–163 �C. IR (KBr) nmax: 3401, 1719, 1545 cm�1, 1H NMR(300 MHz, CDCl3): d 7.35–7.18 (m, 5H, aromatic protons), 5.85–5.83(m, 1H, olefinic proton), 5.50 (dd, J1 ¼ 6.3 Hz, J2 ¼ 2.4 Hz, 1H, protonadjacent to nitro group), 3.89–3.88 (m, 1H), 3.78 (part of an AB system,JAB ¼ 12 Hz, 1H, CH2Cl), 3.63 (part of an AB system, JAB ¼ 12 Hz,1H, CH2Cl), 3.56 (d, J ¼ 6.6 Hz, 1H, methine proton), 3.06 (brs, 1H,�OH), 2.02 (d, J ¼ 2.1 Hz, 3H, CH3), 0.921 (s, 3H, CH3). 13C NMR(100 MHz, CDCl3): d 207.51, 141.96, 137.27, 129.58, 129.08, 129.04,128.12, 87.67, 73.76, 57.46, 53.61, 50.08, 49.61, 21.62, 15.96. Anal.calcd. for C17H18ClNO4: C, 60.81; H, 5.40; N, 4.17%. Found: C,60.24; H, 5.37; N, 4.39%.

Crystal data: C17H18ClNO4, M 335.77, space group, triclinic, P-1,a ¼ 8.332(2), b ¼ 8.495(6), c ¼ 11.871(5), d ¼ 0.71073, a ¼ 108.50(5),

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b ¼ 99.28(3), c ¼ 92.61(4)�, U 782.2(7)3, Z ¼ 2, Dc ¼ 1.426 mg=m3,T ¼ 150(2)K, F(000) ¼ 352, size ¼ 0.36� 0.26� 0.21 mm. Reflect-ions collected=unique: 7184=2693 [R(int) ¼ 0.0205], final R indices[I > 2sigma(I)], R1 ¼ 0.0406, wR2 ¼ 0.1116 R; indices (all data)R1 ¼ 0.0512, wR2 ¼ 0.1222.

3-Chloromethyl-3-hydroxy-8-endo-nitro-7-exo-phenylbicyclo[2.2.2]oct-5-

en-2-one (10a)

The dimer 8a (0.5 g, 1.6 mmol) and trans-b-nitrostyrene (0.945 g,6.3 mmol) in o-dichlorobenzene (5 mL) were heated at 150 �C for 4 h, afterwhich the reaction mixture was charged on a column and chromato-graphed. Elution with petroleum ether–ethyl acetate (85:15) gave theadduct 10a (0.259 g, 27%) as a colorless solid, mp 158–160 �C. IR(KBr) nmax: 3383, 1727, 1540, 1381 cm�1. 1H NMR (400 MHz, CDCl3):d 7.37–7.25 (m, 5H, aromatic protons), 6.67–6.63 (m, 1H, olefinic pro-ton), 6.51–6.48 (m, 1H, olefinic proton), 5.57 (dd, J1 ¼ 6 Hz,J2 ¼ 2.4 Hz, 1H, proton adjacent to nitro group), 4.13–4.11 (m, 1H),3.89 (dd, J1 ¼ 5.6 Hz, J2 ¼ 2.4 Hz, 1H), 3.73 (part of an AB system,JAB ¼ 12.4 Hz, 1H, CH2Cl), 3.62 (part of an AB system, JAB ¼ 12.4 Hz,Hz, 1H, CH2Cl), 3.41 (ddd, J1 ¼ 6.4 Hz, J2 ¼ 2.8 Hz, J3 ¼ 1.2 Hz, 1H),2.98 (s, 1H, -OH). 13C NMR (75 MHz, CDCl3): d 205.09 (CO), 138.22,132.17, 131.50, 129.26, 128.07, 127.88, 85.48, 73.19, 54.35, 50.38, 50.28,45.39. HRMS (m=z) found: 330.0506 (MþþNa); calculated forC15H14NO4NaCl: 330.0509.

3-Chloromethyl-3-hydroxy-5,6-dimethyl-8-endo-nitro-7-exo-

phenylbicyclo[2.2.2]oct-5-en-2-one (10b)

The dimer 8b (0.5 g, 1.3 mmol), trans-b-nitrostyrene (0.8 g, 5.4 mmol),and o-dichlorobenzene (5 mL) were heated at 140 �C for 11 h. Chromato-graphy of the reaction mixture [petroleum ether–ethyl acetate (85:15)]gave the adduct 10b (0.128 g, 14%) as a colorless solid, mp 166–168 �C.IR (KBr) nmax: 3394, 1723, 1552, 1380 cm�1. 1H NMR (400 MHz,CDCl3): d 7.33–7.26 (m, 5H, aromatic protons), 5.50 (dd, J1 ¼ 6.4 Hz,J1 ¼ 2.4 Hz, 1H, proton adjacent to nitro group), 3.86 (d, J ¼ 2.4 Hz,2H), 3.76 (part of an AB system, JAB ¼ 12 Hz, 1H, CH2Cl), 3.52 (partof an AB system, JAB ¼ 12 Hz, 1H, CH2Cl), 3.14 (d, J ¼ 2.4 Hz, 1H),2.94 (s, 1H), 1.92 (s, 3H), 1.89 (s, 3H). 13C NMR (100 MHz, CDCl3): d205.39 (CO), 138.97, 132.65, 131.62, 129.28, 127.99, 127.87, 86.58,73.59, 60.03, 50.86, 50.30, 49.94, 17.93, 16.55. HRMS (m=z) found:358.0824 (MþþNa); calculated for C17H19NO4NaCl: 358.0822.

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3-Chloromethyl-3-hydroxy-5-methyl-8-endo-nitro-7-exo-phenylbicyclo[2.2.2]oct-5-en-2-one (10c)

Heating the dimer 8c (0.5 g, 1.4 mmol) and trans-b-nitrostyrene (0.863 g,5.8 mmol) in o-dichlorobenzene (5 mL) at 140 �C for 8 h followed by chro-matography [petroleum ether–ethyl acetate (88:12)] gave the adduct 10c

(0.220 g, 24%) as a colorless solid, mp 152–154 �C. IR (KBr) nmax:3421, 1732, 1549 cm�1. 1H NMR (400 MHz, CDCl3): d 7.35–7.26 (m,5H, aromatic protons), 6.20–6.18 (m, 1H, olefinic proton), 5.54 (dd,J1 ¼ 5.6 Hz, J2 ¼ 2.4 Hz, 1H, proton adjacent to nitro group), 3.94–3.93 (m, 1H), 3.85 (dd, J1 ¼ 6.4 Hz, J2 ¼ 2.8 Hz,1H), 3.74 (part of anAB system, JAB ¼ 12.4 Hz, 1H, CH2Cl), 3.58 (part of an AB system,JAB ¼ 12.4 Hz, 1H, CH2Cl), 3.29 (dd, J1 ¼ 6.4 Hz, J2 ¼ 2.8 Hz, 1H,methine proton), 3.00 (brs, 1H, -OH), 2.03 (d, J ¼ 1.6 Hz, 3H, CH3).13C NMR (100 MHz, CDCl3): d 205.68 (CO), 142.26, 138.69, 129.31,128.08, 127.91, 123.72, 85.74, 73.30, 54.12, 51.23, 49.97, 49.77, 21.79.HRMS (m=z) found: 344.0679 (MþþNa); calculated for C16H16NO4-NaCl: 344.0666.

3-Hydroxy-1,3,5-trimethyl-8-endo-nitro-7-exo-phenylbicyclo[2.2.2]oct-5-

en-2-one (10d)

The dimer 8d (0.5 g, 1.6 mmol) and trans-b-nitrostyrene (0.983 g,6.6 mmol) in o-dichlorobenzene (5 mL) was heated at 140 �C for 2 h,and the reaction mixture was chromatographed. Elution with petroleumether–ethyl acetate (80:20) gave adduct 10d (0.469 g, 47%) as a colorlesssolid, mp 158–160 �C. IR (KBr) nmax: 3394, 1721, 1544 cm�1. 1H NMR(300 MHz, CDCl3): d 7.32–7.16 (m, 5H, aromatic protons), 5.79–5.76(m, 1H, olefinic proton), 5.52 (dd, J1 ¼ 6.3 Hz, J2 ¼ 2.7 Hz, 1H, protonadjacent to nitro group), 3.57–3.51 (m, 2H), 2.87 (brs, 1H, OH), 1.98(d, J ¼ 1.5 Hz, 3H, �CH3), 1.43 (s, 3H, �CH3), 0.91 (s, 3H, �CH3).13C NMR (75 MHz, CDCl3): d 211.61 (CO), 141.87, 137.56, 129.04,128.80, 127.84, 87.66, 72.11, 57.17, 52.93, 52.70, 25.11, 22.17, 15.82.HRMS (m=z) found: 324.1227 (Mþ þNa); calculated for C17H19NO4Na:324.1212.

3-Chloromethyl-3-hydroxy-1,5-dimethyl-7-exo-(p-methoxy)phenyl-8-

endo-nitro-bicyclo[2.2.2]oct-5-en-2-one (11)

The dimer 4 (0.5 g, 1.3 mmol) and p-methoxy-trans-b-nitrostyrene (0.96 g,6.4 mmol), in o-dichlorobenzene (5 mL) was heated at 160 �C for 3 h,

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after which the reaction mixture was chromatographed. Elution withpetroleum ether–ethyl acetate (90:10) gave adduct 11 (0.351 g, 27%)as a colorless solid, mp 162–164 �C. IR (KBr) nmax: 3388, 1717,1615 cm�1. 1H NMR (300 MHz, CDCl3): d 7.12 (d, J ¼ 6 Hz, 2H, aro-matic protons), 6.84 (d, J ¼ 5.7 Hz, 2H, aromatic protons), 5.84–5.80(m, 1H, olefinic proton), 5.46 (dd, J1 ¼ 6.3 Hz, J2 ¼ 2.1 Hz, 1H, protonadjacent to nitro group), 3.87–3.85 (m, 1H), 3.78 (s, 3H, �OCH3), 3.77(part of an AB System, JAB ¼ 12 Hz, 1H, �CH2Cl), 3.62 (part of anAB system, JAB ¼ 12 Hz, 1H, �CH2Cl), 3.51 (d, J ¼ 6.3 Hz, 1H), 3.12(brs, 1H, -OH), 2.01 (d, J ¼ 1.5 Hz, 3H, �CH3), 0.91 (s, 3H, �CH3).13C NMR (75 MHz, CDCl3): d 207.53 (CO), 159.29, 141.73, 130.04,129.50, 129.18, 114.36, 87.73, 73.70, 56.73, 55.32, 53.72, 49.98, 49.52,21.51, 15.86. HRMS (m=z) found: 388.0916 (Mþ þNa); calculated forC18H20NO5NaCl: 388.0928.

3-Chloromethyl-3-hydroxy-7-exo-(p-methoxy)phenyl-8-endo-

nitrobicyclo[2.2.2]oct-5-en-2-one (12)

The dimer 11a (0.5 g, 1.6 mmol) and p-methoxy-trans-b-nitrostyrene(1.129 g, 7.6 mmol) in o-dichlorobenzene (5 mL) was heated at 160 �Cfor 5 h. Chromatography of the reaction mixture [petroleum ether–ethylacetate (88:12)] gave the adduct 12 (0.243 g, 26%) as a colorless solid, mp160–162 �C. IR (KBr) nmax: 3419, 1719, 1617, 1551 cm�1. 1H NMR(300 MHz, CDCl3): d 7.28–7.20 (m, 2H, aromatic protons), 6.90–6.84(m, 2H, aromatic protons), 6.66–6.58 (m, 1H, olefinic proton), 6.52–6.44 (m, 1H, olefinic proton), 5.52 (dd, J1 ¼ 6 Hz, J2 ¼ 2.7 Hz, 1H, pro-ton adjacent to nitro group), 4.12–4.08 (m, 1H), 3.83 (dd, J1 ¼ 6.3 Hz,J2 ¼ 2.7 Hz,1H), 3.78 (s, 3H, -OCH3), 3.72 (part of an AB system,JAB ¼ 12 Hz, 1H, �CH2Cl), 3.62 (part of an AB system, JAB ¼ 12 Hz,1H, �CH2Cl), 3.36 (ddd, J1 ¼ 6.3 Hz, J2 ¼ 2.4 Hz, J3 ¼ 1.2 Hz,1H),3.07 (brs, 1H, -OH). 13C NMR (75 MHz, CDCl3): d 205.30 (CO),159.26, 132.14, 131.36, 130.25, 129.02, 114.59, 85.65, 73.23, 55.35,54.72, 50.36, 49.75, 45.32. HRMS (m=z) found: 360.0602 (Mþ þNa); cal-culated for C16H16NO5NaCl: 360.0615.

ACKNOWLEDGMENT

We are grateful to Department of Science and Technology, New Delhi,for continued financial support. One of us (R.B.S.) is thankful to Councilof Scientific and Industrial Research, New Delhi, for a research fellow-ship. Thanks are also due to DST for creating a single-crystal X-ray dif-fraction facility.

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9. Chanon, M.; Barone, R.; Baralotto, C.; Julliard, M.; Hendrickson, J. B. Infor-mation theory description of synthetic strategies in the polyquinane series. Theholosynthon concept. Synthesis 1998, 1559–1583.

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