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A SIMPLE AND EFFICIENTREGIOSELECTIVESYNTHESIS OF VARIOUSBICYCLO[n.m.0]ALKANEDIONESSengodagounder Muthusamy a , SrinivasaraoArulananda Babu a & Chidambaram Gunanathan aa Central Salt and Marine Chemicals ResearchInstitute , Silicates and Catalysis Discipline,Bhavnagar, 364 002, IndiaPublished online: 09 Nov 2006.

To cite this article: Sengodagounder Muthusamy , Srinivasarao Arulananda Babu& Chidambaram Gunanathan (2001) A SIMPLE AND EFFICIENT REGIOSELECTIVESYNTHESIS OF VARIOUS BICYCLO[n.m.0]ALKANEDIONES, Synthetic Communications:An International Journal for Rapid Communication of Synthetic Organic Chemistry,31:8, 1205-1211, DOI: 10.1081/SCC-100104005

To link to this article: http://dx.doi.org/10.1081/SCC-100104005

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A SIMPLE AND EFFICIENT

REGIOSELECTIVE SYNTHESIS OF

VARIOUS BICYCLO[n.m.0]ALKANEDIONES

Sengodagounder Muthusamy,* Srinivasarao Arulananda Babu,

and Chidambaram Gunanathan

Silicates and Catalysis Discipline, Central Salt and MarineChemicals Research Institute, Bhavnagar 364 002, India

ABSTRACT

Treatment of the diazo diones 1a–i with a catalyticamount of titanium(IV) chloride furnished regioselectivelythe bicyclo[n.m.0]alkanediones 3a–i in very good yields.

Lewis-acid catalyzed decomposition of diazo ketones has been used asa general strategy for cyclopentenone annelation,1,2 aromatic ring participa-tion,3 homologization of ketones.4 Intramolecular C-H insertion reactions5

of iron complexes tethered to substituted cycloalkanones were used for thesynthesis of bicyclo[n.3.0]alkanones. Bicyclo[5.3.0]decane-2,10-dione wassynthesized in moderate yield using tin(II) chloride6 and triethyloxoniumtetrafluoroborate.7 We herein report a simple and efficient regioselectivemethod using titanium tetrachloride for the synthesis of bicyclo[n.m.0]alkanediones of various ring sizes and substituents. The resulting bicyclo[n.m.0]alkanedione systems are ubiquitous among natural products andmany carbocyclic compounds of widespread interest.

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Copyright & 2001 by Marcel Dekker, Inc. www.dekker.com

SYNTHETIC COMMUNICATIONS, 31(8), 1205–1211 (2001)

*Corresponding author. Fax: þ91 278 566970.

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It was envisaged that the reaction of a diazo ketone with a cyclopen-tanone ring system such as 1a with titanium tetrachloride, in principle, cangenerate either the bicyclo[4.2.0]octane-2,8-dione (3a) via path ‘a’ or themore strained bicyclo[3.2.1]octane-6,8-dione (4a) via path ‘b’ (Scheme).For investigating this reaction, the starting materials 1 were assembledfrom commercially available materials. The mild hydrolysis of ethyl 2-oxo-cyclopentaneacetate was carried out using 5% aqueous KOH solution tofurnish the corresponding 2-oxocyclopentaneacetic acid. On treatment ofthe above prepared acid with ethyl chloroformate and triethylamine, awhite suspension resulted at room temperature. The formed mixed anhy-dride was then treated with freshly prepared ethereal diazomethane at0�–10�C, furnishing diazo dione 1a. The same sequence of reactions wascarried out on the appropriate substrates to furnish diazo diones8 1b–i.Treatment of a 0.072M dichloromethane solution of the diazo ketone 1a

with a catalytic amount of titanium tetrachloride at 0�C for 2min furnishedthe bicyclo[4.2.0]octane-2,8-dione (3a) in very good yield with a highlyregioselective manner (Scheme). The nitrogen evolution takes place immedi-ately on the addition of a catalytic amount of titanium tetrachloride to thediazo solution. In fact, the reaction was completed within a minute andcontinued for another minute. Reactions were performed for other diazoketones 1b–i in a similar manner and furnished the correspondingbicyclo[n.m.0]alkanediones 3b–i with various ring systems and substituentswhere n¼ 4,5,6 and m¼ 2,3. All these reactions were followed by TLC forthe disappearance of a-diazo carbonyl compound. The purification of thereaction mixture was carried out using silica gel column chromatography,

1206 MUTHUSAMY, BABU, AND GUNANATHAN

Scheme.

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affording the corresponding products 3b–i in very good yields. Interestingly,the formation of bicyclic systems with eight- and four-membered fusedring system (entry 3i) was also observed. The results are summarized inthe Table.

The structures of the products were deduced from their interrelatedspectral data. The presence of broad absorption at 3461 cm�1 in FT IR, abroad singlet resonance at � 6.9 in the 1H NMR, and the presence of eightsignals including two olefinic carbons at � 117.7 and 176.2, a carbonylcarbon at � 219.1 in the 13C NMR spectrum for the product 3a clearlyestablished the bicyclo[4.2.0]octane-2,8-dione structure. The above charac-teristic spectral data indicate that one of the carbonyl groups exists as thecorresponding enol form in the solution. The absence of two carbonylgroups, two CH carbons in 13C NMR, and the presence of enol form dis-favor the bridgehead structure 4.

Both the types of rearrangement, i.e., path ‘a’ and path ‘b’, are, inprinciple, possible and in all the reactions only bicyclic 1,3-diketones 3 wereproduced and no detectable amount of the bridgehead diones 4 wereobserved. It was also noted that the diazo ketones 1e,h,i having methylsubstitution on one of the migrating bonds are also afforded the correspond-ing bicyclic compounds 3e,h,i. A mechanistic scheme that may involveO-complexation of the diazo ketone by the titanium tetrachloride asshown in 2, followed by nitrogen loss to produce secondary carbocationand the selective �-bond migration via route ‘a’, afforded the product 3.In conclusion, a novel and efficient regioselective method for the synthesis ofbicyclo[n.m.0]alkanediones comprising various ring sizes and substituentswas established. Application of this methodology to the synthesis of naturalproduct is in progress in our laboratory.

BICYCLO[n.m.0]ALKANEDIONES 1207

Table. Synthesis of Bicyclo[n.m.0]alkanediones 3

Substrate n�3 n�4 m�2 R1 R2 Yielda (%)

a 1 0 0 H H 84b 1 0 1 H CH3 81

c 2 1 0 H H 71d 2 1 1 H H 79e 2 1 1 CH3 CH3 83

f 3 2 1 H H 80g 3 2 1 H CH3 72h 3 2 1 CH3 h 75

i 3 2 0 CH3 H 69

aYields (unoptimized) refer to isolated and chromatographically pure compounds 3.

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EXPERIMENTAL

IR spectra were recorded on a Perkin Elmer Spectrum GX FT-IRspectrophotometer. 1H NMR and 13C NMR spectra were recorded on aBruker DPX 200 (200MHz and 50MHz, respectively) spectrometerand referenced to TMS. Carbon types were determined from DEPT13C NMR experiments. Elemental analyses were performed on a PerkinElmer Model 2400 analyzer. Care was taken to prevent from light duringthe course of reaction in the synthesis of diazo compounds and its furtherconversion.

General Procedure for the Synthesis of Bicyclic 1,3-Diketones (3)

The appropriate diazo carbonyl compound 1a–i (0.7mmol) was takenin 10mL of dry dichloromethane solution (dried over P2O5) and cooled to0�C under argon atmosphere with magnetic stirring. To this stirred reac-tion mixture, a catalytic amount of titanium tetrachloride was added. Theevolution of nitrogen took place immediately and the reaction was fol-lowed by TLC, which showed the disappearance of the starting materialwithin a minutes duration. The reaction mixture was allowed to continuefor one more minute and quenched with 5mL of ice-cold water. Theorganic layer was separated; the aqueous layer was saturated with NaCland extracted twice with ether. The combined organic layer was washedwith brine solution and dried over anhydrous magnesium sulfate. Removalof the solvent left a residue, which was purified on a short silica gel columnfurnishing the corresponding bicyclic 1,3-diketones 3a–i in very goodyields. The following compounds were prepared according to the aboveprocedure.

Bicyclo[4.2.0]octane-2,8-dione (3a)

Colorless liquid. IR(CH2Cl2): �max 3461, 2966, 2879, 1740, 1655, 1453,1410, 1324, 1264, 1166, 1132, 1065 cm�1. 1H NMR (200MHz, CDCl3): �6.92 (1H, br s, OH), 3.15–3.29 (1H, m), 2.65–2.75 (2H, m), 1.99–2.55(4H, m), 1.56–1.83 (2H, m). 13C NMR (50MHz, CDCl3): � 219.1 (C,C¼O), 176.2 (C, C¼COH), 117.7 (C, C¼C), 42.1 (CH), 38.2 (CH2), 37.0(CH2), 33.6 (CH2), 22.5 (CH2). Anal. calc. for C8H10O2: C 69.95, H 7.30.Found: C 69.82, H 7.17%.

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8-Methylbicyclo[4.3.0]nonane-2,9-dione (3b)

Colorless liquid. IR(CH2Cl2): �max 3435, 2933, 1747, 1678, 1619, 1456,1377, 1212, 1155, 915 cm�1. 1H NMR (200MHz, CDCl3): � 8.40 (1H, br s,OH), 2.61–2.83 (1H, m), 2.28–2.49 (3H, m), 1.56–2.26 (5H, m), 1.29–1.42(1H, m), 1.15 (3H, d, J¼7.6Hz, CH3)

13C NMR (50MHz, CDCl3): � 211.8(C, C¼O), 176.2 (C, C¼COH), 111.8 (C, C¼C), 42.4 (CH), 37.5 (CH2), 34.4(CH2), 29.9 (CH2), 27.9 (CH2), 22.4 (CH2), 16.4 (CH3). Anal. calc. forC10H14O2: C 72.26, H 8.49. Found: C 72.19, H 8.37%.

Bicyclo[5.2.0]nonane-2,9-dione (3c)

Colorless liquid. IR(CH2Cl2): �max 3396, 2934, 2864, 1707, 1515, 1410,1278, 1233, 1172, 1088, 961 cm�1. 1H NMR (200MHz, CDCl3): � 8.73 (1H,br s, OH), 2.75–2.85 (2H, m), 2.21–2.43 (2H, m), 2.09–2.18 (3H, m), 1.57–1.86 (3H, m), 1.30–1.51 (1H, m). 13C NMR (50MHz, CDCl3): � 211.7 (C,C¼O), 178.8 (C, C¼COH), 117.1 (C, C¼C), 47.5 (CH), 42.4 (CH2), 34.9(CH2), 34.4 (CH2), 28.4 (CH2), 25.8 (CH2). Anal. calc. for C9H12O2: C71.03, H 7.95. Found: C 70.89, H 8.05%.

Bicyclo[5.3.0]decane-2,10-dione (3d)6,7

Colorless liquid. IR(CH2Cl2): �max 3340, 2924, 2854, 1726, 1652, 1451,1391, 1323, 1230, 1192, 1116, 1075, 904 cm�1. 1H NMR (200MHz, CDCl3):� 13.88 (1H, br s, OH), 2.80–2.84 (1H, m), 2.35–2.48 (3H, m), 2.08–2.18 (1H,m), 1.84–2.05 (3H, m), 1.23–1.52 (5H, m). 13C NMR (50MHz, CDCl3): �203.9 (C, C¼O), 183.3 (C, C¼COH), 115.0 (C, C¼C), 39.8 (CH), 37.5(CH2), 36.5 (CH2), 36.3 (CH2), 29.8 (CH2), 28.6 (CH2), 24.6 (CH2).

3,9-Dimethylbicyclo[5.3.0]decane-2,10-dione (3e)

Colorless liquid. IR(CH2Cl2): �max 3481, 2926, 2846, 1726, 1652, 1451,1390, 1231, 1118, 1041 cm�1. 1H NMR (200MHz, CDCl3): � 12.07 (1H, brs, OH), 2.76–3.09 (1H, m), 2.01–2.72 (3H, m), 1.71–1.98 (4H, m), 1.31–1.57(3H, m), 1.25 (3H, d, J¼7.1Hz, CH3), 1.18 (3H, d, J¼7.6Hz, CH3).13C NMR (50MHz, CDCl3): � 204.2 (C, C¼O), 182.2 (C, C¼COH),114.0 (C, C¼C), 39.8 (CH), 38.0 (CH), 35.6 (CH), 34.1 (CH2), 28.7(CH2), 27.6 (CH2), 24.9 (CH2), 16.4 (CH3), 15.8 (CH3). Anal. calc. forC12H18O2: C 74.19, H 9.34. Found: C 74.26, H 9.31%.

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Bicyclo[6.3.0]undecane-2,11-dione (3f)

Colorless liquid. IR(CH2Cl2): �max 3463, 2929, 2860, 1726, 1655, 1455,1385, 1314, 1244, 1169, 911 cm�1. 1H NMR (200MHz, CDCl3): � 13.74 (1H,br s, OH), 2.90–2.95 (1H, m), 2.09–2.52 (4H, m), 1.72–1.77 (5H, m), 1.25–1.69 (5H, m). 13C NMR (50MHz, CDCl3): � 206.7 (C, C¼O), 178.1 (C,C¼COH), 114.0 (C, C¼C), 38.7 (CH), 37.8 (CH2), 35.1 (CH2), 32.1 (CH2),28.6 (CH2), 26.7 (CH2), 25.6 (CH2), 25.3 (CH2). Anal. calc. for C11H16O2: C73.30, H 8.95. Found: C 73.48, H 8.84%.

10-Methylbicyclo[6.3.0]undecane-2,11-dione (3g)

Colorless liquid. IR(CH2Cl2): �max 3402, 2928, 2858, 1742, 1650, 1353,1376, 1240, 1096, 1035 cm�1. 1H NMR (200MHz, CDCl3): � 13.82 (1H, brs, OH), 2.87–3.02 (1H, m), 2.09–2.79 (3H, m), 1.56–1.78 (6H, m), 1.25–1.53(4H, m), 1.14 (3H, d, J¼7.5Hz, CH3).

13C NMR (50MHz, CDCl3): � 207.2(C, C¼O), 177.9 (C, C¼COH), 115.1 (C, C¼C), 39.0 (CH), 35.1 (CH2), 34.3(CH), 32.1 (CH2), 28.5 (CH2), 26.6 (CH2), 25.9 (CH2), 25.1 (CH3), 16.6(CH3). Anal. calc. for C12H18O2: C 74.19, H 9.34. Found: C 74.11, H 9.39%.

3-Methylbicyclo[6.3.0]undecane-2,11-dione (3h)

Colorless liquid. IR(CH2Cl2): �max 3462, 2930, 2860, 1738, 1656, 1450,1374, 1243, 1091, 1045 cm�1. 1H NMR (200MHz, CDCl3): � 12.32 (1H, brs, OH), 2.57–3.02 (3H, m), 1.79–2.52 (5H, m), 1.25–1.77 (6H, m), 1.21 (3H,d, J¼7.5Hz, CH3)

13C NMR (50MHz, CDCl3): � 206.2 (C, C¼O), 176.9 (C,C¼COH), 114.3 (C, C¼C), 38.7 (CH), 37.7 (CH2), 35.2 (CH), 32.1 (CH2),29.0 (CH2), 26.7 (CH2), 25.9 (CH2), 25.2 (CH2), 17.3 (CH3). Anal. calc. forC12H18O2: C 74.19, H 9.34. Found: C 74.02, H 9.21%.

3-Methylbicyclo[6.2.0]decane-2,10-dione (3i)

Colorless liquid. IR(CH2Cl2): �max 3240, 2934, 2860, 1704, 1615, 1410,1278, 1239, 1134, 930 cm�1. 1H NMR (200MHz, CDCl3): � 13.31 (1H, br s,OH), 2.80–3.01 (2H, m), 2.34–2.69 (4H, m), 1.84–2.28 (3H, m), 1.25–1.75(3H, m), 1.12 (3H, d, J¼7.5Hz, CH3).

13C NMR (50MHz, CDCl3): � 207.7(C, C¼O), 184.1 (C, C¼COH), 115.0 (C, C¼C), 42.0 (CH2), 38.7 (CH), 37.7(CH2), 35.3 (CH), 31.7 (CH2), 27.8 (CH2), 24.7 (CH2), 17.0 (CH3). Anal.calc. for C11H16O2: C 73.30, H 8.95. Found: C 73.21, H 8.76%.

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ACKNOWLEDGMENTS

This research was supported in part by the Department of Science andTechnology, New Delhi. We thank Dr. P. K. Ghosh, Director, and R. V.Jasra, Head of the Division, for their encouragement shown in this work.S. A. B. and C. G. wish to acknowledge the CSIR for a fellowship.

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Soc. 1981, 103, 1996.3. Smith, III, A.B.; Dieter, R.K. J. Am. Chem. Soc. 1981, 103, 2017.4. Regitz, M.; Mass, G. Diazo Compounds-Properties and Synthesis;

Academic Press, Inc.: New York, 1986; 148–165.5. Ishii, S.; Helquist, P. Synlett 1977, 508.6. Padwa, A.; Hornbuckle, S.F.; Zhang Z.; Zhi, L. J. Org. Chem. 1990,

55, 5297.7. Mock, W.L.; Hartman, M.E. J. Org. Chem. 1977, 42, 459.8. Muthusamy, S.; Babu, S.A.; Gunanathan, C.; Suresh, E.; Dastidar, P.;

Jasra, R.V. Tetrahedron 2000, 56, 6307.

Received May 15, 2000

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