Tetrahedron Letters 54 (2013) 3302–3305

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Tetrahedron Letters

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Synthesis and esterification reactions of aryl diazomethanes derived fromhydrazone oxidations catalyzed by TEMPO

Carolina Perusquía-Hernández, Gonzalo R. Lara-Issasi, Bernardo A. Frontana-Uribe, Erick Cuevas-Yañez ⇑Centro Conjunto de Investigación en Química Sustentable UAEM–UNAM, Carretera Toluca-Atlacomulco Km. 14.5, Toluca, Estado de México 50200, Mexico

a r t i c l e i n f o

Article history:Received 14 February 2013Revised 16 April 2013Accepted 19 April 2013Available online 27 April 2013

Keywords:HydrazoneDiazo compoundOxidationTEMPOEster

0040-4039/$ - see front matter � 2013 Published byhttp://dx.doi.org/10.1016/j.tetlet.2013.04.079

⇑ Corresponding author. Tel.: +52 722 276 66 10x7E-mail address: ecuevasy@uaemex.mx (E. Cuevas-

a b s t r a c t

Diverse hydrazones were oxidized to the corresponding diazoalkanes using sodium hypochlorite in thepresence of catalytic amounts of TEMPO (2,2,6,6-tetramethylpiperidinyloxy). A library of diverse benzhy-dryl esters and analogues was prepared from diazoalkanes obtained by this procedure.

� 2013 Published by Elsevier Ltd.

N2 OAcNaOCl

TEMPO cat.NNH2 AcOH

Diazoalkanes are valuable and interesting synthetic materialswhich represent an important source of carbene/carbenoid inter-mediates as well as other precursors.1 One of the well-knownmethods to prepare diazoalkanes involves the oxidation of diversehydrazones.2 However, most of the oxidation protocols for hydra-zones use transition metal based oxidizers, such as HgO,3 Ag2O,4

CrO2,5 Ni2O3,6 KMnO4-Al2O3,7 MnO2,8 Pb(AcO)4,9 and triphenylbis-muth carbonate.10 Due to the inherent toxicity of transition metals,many research groups have developed environmentally friendlyprocedures based on the use of less toxic oxidizing agents suchas OXONE™,11 calcium hypochlorite (only for synthesis of diazok-etones from hydrazono carbonyl compounds),12 DMSO–(COCl)2,13

as well as hypervalent iodine reagents.14–17

In connection with a current synthetic study, we required an ar-ray of aryldiazoalkanes in which the aryl portion of the moleculewas widely varied through a nonexpensive method from readilyaccessible reagents avoiding transition metals. Searching the avail-able oxidation procedures, we were attracted by the oxoammoni-um ion mediated oxidations derived from nitroxyl radicals; animportant kind of intermediates with applications as mild oxi-dants.18 The most notable example of nitroxyl radical is TEMPO(2,2,6,6-tetramethylpiperidinyloxy), used mainly as catalyst inselective oxidation of primary alcohols to aldehydes.19 Inspiredby these previous reports, we initiated an investigation about theTEMPO catalyzed oxidations on hydrazones. This Letter describes

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734; fax: +52 722 217 5109.Yañez).

the successful adaptation of this methodology to the synthesis ofaryldiazomethanes and their corresponding arylmethyl esters.

In a model study, benzophenone hydrazone 1 was treated withan excess of 13% sodium hypochlorite solution in the presence ofcatalytic amounts TEMPO (Scheme 1). After 5 min at 0 �C, the char-acteristic reddish color associated with the diazo group appeared.Purification of the reaction mixture afforded a violet oil whichwas identified as diphenyldiazomethane 2 that shows the diazogroup band C@N@N in 2050 cm�1 and a signal in the 13C NMRspectrum in 54 ppm corresponding to the diazo group carbon. Asdiazoalkanes are unstable to air and ambient conditions, diphenyl-diazomethane 2 was reacted with acetic acid in order to determinethe reaction yield.13 Preliminary experiments demonstrated thatbenzhydryl ester 3 was obtained as major product in this step.

The success of the process motivated us to optimize some reac-tion conditions. The experiments in Table 1 showed that tempera-ture and reaction time play an important role in the reaction; thebest yield was obtained when the reaction was carried out at�5 �C for 1 h (Table 1, entry 8). On the other hand, both calciumand sodium hypochlorite were tested as oxidizing agents in this

Ph Ph Ph PhKBr, NaHCO3

Temp.

Ph Ph1 2 3

Scheme 1. Synthesis of benzhydryl ester 3 from diphenyldiazomethane 2 andbenzophenone hydrazone 1.

Table 3Effect of catalyst, co-oxidizing agent, base, and KBr

Entry Catalystratio(% mol)

NaOCl/hydrazone(mmol)

NaHCO3/hydrazone(mmol)

KBr/hydrazone(mmol)

Yield(%)

1 3.8 3.0 0.3 0.2 622 3.8 3.0 0.6 0.2 733 3.8 3.0 1.0 0.2 604 3.8 3.0 0.6 0.1 435 3.8 3.0 0.6 0.2 806 3.8 3.0 0.6 0.4 727 1 3.0 0.6 0.2 528 2 3.0 0.6 0.2 919 4 3.0 0.6 0.2 4810 2 1 0.6 0.2 7511 2 2 0.6 0.2 7012 2 3.5 0.6 0.2 95

Table 1Effect of temperature and reaction time

Entry Catalyst ratio(% mol)

Temperature(�C)

Reaction time(min)

Yield(%)

1 3.8 0 15 322 3.8 0 30 533 3.8 0 45 604 3.8 0 60 835 3.8 0 90 106 3.8 5 60 227 3.8 0 60 838 3.8 �5 60 929 3.8 �10 60 86

Table 2Effect of the oxidizing agent

Entry Catalyst ratio(% mol)

OxidizingAgent

Oxidizing agent/hydrazone (mmol)

Yield(%)

1 3.8 Ca(ClO)2 1.0 522 3.8 Ca(ClO)2 2.0 573 3.8 Ca(ClO)2 3.0 654 3.8 Ca(ClO)2 4.0 585 3.8 NaClO 1.0 806 3.8 NaClO 2.0 707 3.8 NaClO 3.0 928 3.8 NaClO 4.0 85

NNH2

NaOCl

KBr, NaHCO3Temp.

TEMPO cat.

N2

AcOHOAc

12 13 14

Scheme 2. Synthesis of bornyl acetate 14 from diazoalkane 13 and camphorhydrazone 12.

Ph Ph

N2

NaOCl

KBr, NaHCO3

Temp.

TEMPO cat.

Ph Ph

NNH2 pyrazole

1 215

NN

Ph PhFe-Cu nano

Scheme 3. Synthesis of pyrazole 15 from diphenyldiazomethane 2 and benzophe-none hydrazone 1.

R1 R2

N2

R1 R2

OCOR3NaOCl

KBr, NaHCO3

-5°C

TEMPO cat.

R1 R2

NNH2 R3CO2H

Scheme 4. Synthesis of benzhydryl esters.

C. Perusquía-Hernández et al. / Tetrahedron Letters 54 (2013) 3302–3305 3303

process. Although calcium hypochlorite is relatively morestable, the best results were observed using sodium hypochlorite(Table 2).

Table 4Benzhydryl esters prepared via Scheme 4

Compound R1 R2 R3

3 Ph Ph CH3

4 Ph Ph Ph5 Ph Ph 4-NO2C6H4

6 Ph Ph 3-NO2C6H4

7 Ph Ph 3-CH3C6H4

8 Ph CH3 CH3

9 CH3 CH3 Ph

10 Ph PhOC

11 Ph Ph 2-Naphthyl12 Ph Ph 4-CH3C6H4

13 Ph Ph 4-ClC6H4

14 Ph Ph 3-ClC6H4

15 4-ClC6H4 H CH3

16 4-ClC6H4 H Ph

In addition, other additives (TEMPO, NaHCO3, KBr) were evalu-ated. Thus, the yield of ester 3 was improved to 95% (Table 3).Using these optimized conditions, a series of benzhydryl esterswere prepared from diazoalkanes which in turn were synthesizedfrom diverse hydrazones (Scheme 4 and Table 4). All the com-pounds were fully characterized by the conventional spectroscopictechniques.20 Not only was this process readily applicable to thesynthesis of benzhydryl esters from aryl diazomethanes. For exam-ple, isopropyl ester derived from diazopropane was successfullyprepared by this procedure (Table 4, compound 9). Moreover, ste-rically hindered esters such as bornyl acetate 14 were preparedfrom diazolakane 13 which in turn was obtained from (±)-camphorhydrazone 12 (Scheme 2).33

This synthesis of functionalized benzhydryl esters has oneimportant limitation. Substrates with sensitive groups such as freealcohols, amines, and aldehydes did not give the desired esters,affording probably other oxidation side products.

On the other hand, we noted azine formation in most of cases,similar to those found by Myers and Furrow,17 and probablythrough a diazoalkane oxidation–dimerization mechanism, as pre-viously described by Sharma34 and Shechter and co-workers.35

Other kind of reactions that involves diazoalkanes is thecarbenoid insertion to heterocyclic rings. In this regard, our group

m.p. (�C) m.p. lit. (�C)ref. Yield (%)

40 39–4121 9589 88–8922 81132 131–13223 7395 ND24 5579 ND24 79Oil Oil25 74Oil Oil26 62

H288 89–9027 63

105 ND28 50109 11029 7587 86.5–8830 70115 115–11731 55Oil Oil32 30Oil Oil27 38

NO

NO

Cl

NO

NN O

N H

NN OH

NNOH

Cl2

NNH2

N N

Cl2

Cl

+B

BH

1617

18

20

19

21

22

23

Scheme 5. Reaction mechanism and catalytic cycle.

3304 C. Perusquía-Hernández et al. / Tetrahedron Letters 54 (2013) 3302–3305

reported carbenoid insertions to imidazole rings using p-toluene-sulfonylhydrazones as diazo compound sources,36 as well as theuse of silver nanoparticles as catalysts in these processes.37 There-fore, we attempted to use diazolakanes synthesized by TEMPO cat-alyzed hydrazone oxidations to the synthesis of alkylpyrazoles. Inthis case, diphenyldiazomethane 2 was treated with pyrazole inthe presence of a catalytic amount of iron–copper nanoparticles,38

obtaining benzhydryl pyrazole 1539 in 50% yield (Scheme 3). Thisresult shows that 1-alkyl pyrazoles could be synthesized throughmetal catalyzed reactions and diazoalkanes prepared in situ fromTEMPO catalyzed oxidations.

A rational mechanistic explanation of this process should becentered in the role of TEMPO catalyst. According to Ramstrom40

and Sheldon,19 oxoammonium ion 18 is formed when TEMPO ni-troxyl radical 16 is reacted with chlorine derived from sodiumhypochlorite (Scheme 5). Then, hydrazone 19 is incorporated intooxoammonium ion 18, generating the intermediate 20. The subse-quent hydrogen transfer affords the intermediate 21 which is dis-proportionated to diazocompound 22 and hydroxy TEMPO 23. Inthe final step, hydroxy TEMPO 23 is re-oxidized by chlorine tothe intermediates 17 and 18, respectively, completing the catalyticcycle.

In summary, hydrazones are easily converted into diazoalkanesthrough a novel procedure which uses sodium hypochlorite asgreen oxidizing agent and TEMPO as catalyst. In addition, diazoalk-anes prepared in this work were used as starting materials to pre-pare some esters and benzhydryl pyrazole 15 with moderate–goodyields. This new diazoalkane synthesis is effected under mild con-ditions, has good functional group tolerance, presents some advan-tages in comparison with other methods and finally is broad inscope. These characteristics suggest that this route to diazoalkanesand esters will enjoy widespread application.

Acknowledgments

Financial support from CONACYT (Project No. 135053) is grate-fully acknowledged. The authors would like to thank Signa S.A. deC.V. for some graciously donated solvents and reagents and to N.Zavala, A. Nuñez, and L. Triana for the technical support.

References and notes

1. Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for OrganicSynthesis with Diazo Compounds: From Cyclopropanes to Ylides; Wiley: NewYork, 1998. p. 10.

2. Zollinger, H. Diazo Chemistry II: Aliphatic, Inorganic and OrganometallicCompounds; VCH: Weinheim, 1995. p. 34.

3. (a) Andrews, S. D.; Day, A. C.; Raymond, P.; Whiting, M. C. Org. Synth. Collect. Vol.1988, 6, 392; (b) Smith, L. I.; Howard, K. L. Org. Synth. Collect. Vol. 1955, 3, 351.

4. Schroeder, W.; Katz, L. J. Org. Chem. 1954, 19, 718.5. Kwang, Y. K.; Ji, Y. K. Bull. Korean Chem. Soc. 1999, 20, 771.6. Nakagawa, K.; Onoue, H.; Minami, K. Chem. Commun. 1966, 730.7. Lee, K. H.; Ko, K. Y. Bull. Korean Chem. Soc. 2006, 27, 185.8. (a) Doyle, M. P.; Yan, M. J. Org. Chem. 2002, 67, 602; (b) Denton, J. R.;

Sukumaran, D.; Davies, H. M. L. Org. Lett. 2007, 9, 2625.9. Holton, T. L.; Schechter, H. J. Org. Chem. 1995, 60, 4725.

10. (a) Padwa, A.; Rodriguez, A.; Tohidi, M.; Fukunaga, T. J. Am. Chem. Soc. 1983,105, 933; (b) Barton, D. H. R.; Lester, D. J.; Motherwell, W. B.; Papoula, M. T. B. J.Chem. Soc. 1979, 705.

11. Curini, M.; Rosati, O.; Pisani, E. Tetrahedron Lett. 1997, 38, 1239.12. Morrison, H.; Danishefsky, S.; Yates, P. J. Org. Chem. 1961, 26, 2617.13. (a) Javed, M. I.; Brewer, M. Org. Lett. 2007, 9, 1789; (b) Javed, M. I.; Brewer, M.

Org. Synth. 2008, 85, 189.14. Bedford, C. D.; Bruckmann, E. M.; Smith, P. A. S. J. Org. Chem. 1981, 46, 679.15. Ter Wiel, M. K. J.; Vicario, J.; Davey, S. G.; Meetsma, A.; Feringa, B. L. Org. Biomol.

Chem. 2005, 3, 28.16. Li, X. Q.; Zhang, C. Synthesis 2009, 1163.17. Furrow, M. E.; Myers, A. G. J. Am. Chem. Soc. 2004, 126, 12222.18. Adam, W.; Saha-Moller, C. R.; Ganeshpure, P. A. Chem. Rev. 2001, 101, 3499.19. Sheldon, R. A.; Arends, I. W. C. E.; Ten Brink, G. J.; Dijksman, A. Acc. Chem. Res.

2002, 35, 774.20. Typical procedure for the oxidation of hydrazones-synthesis of benzhydryl

esters. A mixture of the appropriate hydrazone (1 mmol), NaHCO3 (0.052 g,0.6 mmol), KBr (0.024 g, 0.2 mmol), and TEMPO (0.003 g, 0.02 mmol) in CH2Cl2

(2 mL) was stirred at �5 �C. A 13% solution of NaOCl (2 mL, 3.5 mmol) wasadded, and the resulting reaction mixture was stirred at �5 �C for 1 h. Theviolet organic layer was separated and cooled to �5 �C again. Then, thecorresponding carboxylic acid (1 mmol) was added portionwise. A vigorousevolution of nitrogen occurred, and the mixture was allowed to warm to roomtemperature and stirred for 15 min. A saturated solution of NaHCO3 (10 mL)was added and the organic layer was extracted with ether (3 � 5 mL). Thecombined organic layers were dried over anhydrous Na2SO4. The solvent wasremoved in vacuo and the product was purified by flash columnchromatography (SiO2, hexane/ethyl acetate 9:1). Selected spectral data.Compound 3: 1H NMR (CDCl3, 500 MHz) d: 2.20 (s, 3H), 6.97 (s, 1H), 7.31–7.87 (m, 10H); 13C NMR (CDCl3, 125 MHz) d: 21.3 (CH3), 77.3 (CH), 127 (CH),127.9 (CH), 127.9 (CH), 128 (CH), 128.3 (CH), 128.6 (CH), 128.7 (CH), 129.3(CH), 129.6 (CH), 130 (CH), 140.2 (CC)29.3170.050 (C7); 138.236 (C2);140.2(C), 159.0(C), 170. 0 (C); MS [EI+] m/z (RI%): 226 [M]+ (7); IR: (ATR,cm�1) 1750, 1624. Compound 4: 1H NMR (CDCl3, 500 MHz) d: 7.17 (s, 1H),7.31–7.87 (m, 12H), 8.12 (m, 2H); 13C NMR (CDCl3, 125 MHz) d: 78.3 (CH),

C. Perusquía-Hernández et al. / Tetrahedron Letters 54 (2013) 3302–3305 3305

127.3 (CH), 127.9 (CH), 128.3 (CH), 128.7 (CH), 129.3 (CH), 130.0 (CH), 131.9(C), 134.2 (C), 138.236 (C),168. 3 (C); MS [EI+] m/z (RI%): 288 [M]+ (10); IR:(ATR, cm�1) 1690, 1650. Compound 5: 1H NMR (CDCl3, 500 MHz) d: 7.14 (s, 1H,CH) 7.28–7.48 (m, 12H), 7.89 (d, J = 8 Hz, 2H). 13C NMR (CDCl3, 125 MHz) d 78.5(CH), 123.6 (CH), 127.1 (CH), 128.3 (CH), 128.3 (CH), 128.7 (CH), 130.7 (CH)130.8 (CH), 132.4 (CH), 135.5 (CH), 137.6 (CH), 139.5 (CH), 140.2 (CC), 150.6(CH), 163.7 (C), 176.7 (C); MS [EI+] m/z (RI%): 333 [M]+ (7); IR: (ATR, cm�1)1720, 1526, 1493, 1277, 1138. Compound 6: 1H NMR (CDCl3, 500 MHz) d: 7.16(s, 1H), 7.23–7.82 (m, 12H), 8.47 (m, 1H), 8.96 (m, 1H). 13C NMR (CDCl3,125 MHz) d 79.5 (CH), 123.5 (CH), 126.3 (CH), 128.2 (CH), 129.3 (CH), 129.6(CH), 131 (CH) 136 (CH), 140.2 (C), 147.8 (C), 169.8 (C); MS [EI+] m/z (RI%): 333[M]+ (10); IR: (ATR, cm�1) 1720, 1526, 1493, 1277, 1138. Compound 7: 1H NMR(CDCl3, 500 MHz) d 2.39 (s, 3H) 7.12 (s, 1H) 7.22–7.95 (m, 14H); 13C NMR(CDCl3, 125 MHz) d 21.3 (CH3), 77.3 (CH), 127.1 (CH), 127.8 (CH), 127.9 (CH),128 (CH), 128.2 (CH), 128.3 (CH), 128.5 (CH), 128.6 (CH), 129.3 (CH), 130 (CH),130.1 (CH) 130.3 (CH), 132.4 (CH) 133.9 (C), 137.6 (C), 138.2 (C), 140.35 (C),165.75 (C); MS [EI+] m/z (RI%): 302 [M]+ (15); IR: (ATR, cm�1) 1719, 1316, 1196.Compound 8: 1H NMR (CDCl3, 500 MHz) d 1.22 (d, 3H), 2.31 (s, 3H), 3.77 (q,1H), 7.40 (m, 3H), 7.86 (m, 2H); 13C NMR (CDCl3, 125 MHz) d 15.0 (CH3), 31.0(CH3), 69.9 (CH), 126.5 (CH), 128.3, (CH), 129.5 (CH). 138.4 (C), 168.7 (C); MS[EI+] m/z (RI%): 164 [M]+ (10); IR: (ATR, cm�1) 2928, 1741, 1028, 697.Compound 9: 1H NMR (CDCl3, 500 MHz) d 1.05 (d, 6H), 3.98 (m, 1H), 7.40 (m,3H), 7.89 (m, 2H); 13C NMR (CDCl3, 125 MHz) d 20.7 (CH3), 68.3 (CH), 128.4(CH), 129.5 (CH), 130.1 (CH), 133.6 (C), 172.5 (C); MS [EI+] m/z (RI%): 164 [M]+

(15); IR: (ATR, cm�1) 2964, 1739. Compound 10: 1H NMR (CDCl3, 500 MHz) d4.83 (s, 2H), 7.00 (s, 1H) 7.21–7.80 (m, 17H); 13C NMR (CDCl3, 125 MHz) d 65.5(CH2),77.8 (CH), 107.2 (CH), 118.6 (CH), 124.1 (CH), 126.4 (CH), 126.9 (CH),127.1 (CH) 127.6 (CH), 128.13 (CH), 128.2 (CH), 128.5 (CH), 129.7 (CH), 130.6(C), 132.4 (CH), 137.6 (CH), 139.4 (CH), 140.5 (C), 157.2 (C), 196.745 (C); MS[EI+] m/z (RI%): 368 [M]+ (5); IR: (ATR, cm�1) 1737, 1277, 1173. Compound 11:1H NMR (CDCl3, 500 MHz) d 7.19 (s, 1H) 7.24–8.70 (m, 17H, ArH); 13C NMR(CDCl3, 125 MHz) d 77.5 (CH), 125.3 (CH), 126.7 (CH), 127.2 (CH), 127.8 (CH),128.0 (CH), 128.2 (CH), 128.2 (CH), 128.3 (CH), 128.6 (CH), 131.3 (CH), 132.4(CH), 132.5 (CH), 132.6 (C), 137.2 (C), 165.7 (C); MS [EI+] m/z (RI%): 338 [M]+

(15); IR: (ATR, cm�1) 1714, 1278, 1156. Compound 12: 1H NMR (500 MHz,CDCl3) d 2.32 (s, 3H), 7.12 (s, 1H), 7.30 (d, J = 8.4 Hz, 2H), 7.32–7.97 (m, 12 H);13C NMR (CDCl3, 125 MHz) d 22.1 (CH3), 77.2 (CH), 127.3 (CH), 127.7 (CH), 1278(CH), 128.1 (CH), 128.3 (CH), 128.5 (CH), 128.6(CH), 128.7 (CH), 129.3 (CH),130.0 (CH), 130.1 (CH) 130.3 (CH), 132.4 (CH) 133.9 (C), 137.6 (C), 138.2 (C),140.35 (C), 165.75 (C); MS [EI+] m/z (RI%): 302 [M]+ (5); IR: (ATR, cm�1) 1720,1315, 1196. Compound 13: 1H NMR (CDCl3, 500 MHz) d: 7.15 (s, 1H), 7.31–7.54(m, 12H), 8.14 (d, J = 8.1 Hz, 2H); 13C NMR (CDCl3, 125 MHz) d: 78.9 (CH), 127.3(CH), 128.1 (CH), 128.8 (CH), 129.3 (CH), 131.5 (CH), 133.9 (C), 134.2 (C), 138.6(C),166. 35 (C); [EI+] m/z (RI%): 322 [M]+ (15); IR: (ATR, cm�1) 1710; Compound14: 1H NMR (CDCl3, 500 MHz) d: 7.10 (s, 1H), 7.31–7.67 (m, 12H), 8.02 (m, 1H),8.15 (d, J = 8.1 Hz, 1H); 13C NMR (CDCl3, 125 MHz) d: 78.1 (CH), 127.2 (CH),

127.8, (CH), 128.1 (CH), 128.8 (CH), 129.3 (CH), 129. 8 (CH), 131.8 (CH), 133.8(C), 134.25 (C), 139.2 (C),166. 35 (C); [EI+] m/z (RI%): 322 [M]+ (10); IR: (ATR,cm�1) 1715. Compound 15: 1H NMR (500 MHz, CDCl3) d 2.15 (s, 3H), 5.09 (s,2H), 7.56 (d, J = 8.2 Hz, 1H), 8.05 (dd, J = 8.2 Hz, 2H). 13C NMR (127.5 MHz,CDCl3) d 21.5 (CH3), 65.9 (CH2), 128.5 (2�CH), 128.9 (2�CH), 134.2 (C), 135.2(C), 170.1 (C); [EI+] m/z (RI%): 184 [M]+ (20); IR: (ATR, cm�1) 1735. Compound16: 1H NMR (500 MHz, CDCl3) d 5.30 (s, 2H), 7.34 (m, 4H), 7.41 (m, 2H), 7.56 (d,J = 7.4 Hz, 1H), 8.05 (dd, J = 8.4 Hz, 2H). 13C NMRNMR (127.5 MHz, CDCl3) d65.9 (CH2), 128.5 (2�CH), 128.9 (2�CH), 129.6 (2�CH), 129.8 (2�CH), 130.0(C), 133.2 (CH), 134.2 (C), 134.7 (C), 166.3 (C). MS [EI+] m/z (RI%): 246 [M]+ (10);IR: (ATR, cm�1) 1694.

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