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May 2, 2012 - product of a 1,3-dicarbonyl dianion of a b-keto ester with an aldehyde, for the synthesis of pyrone derivatives via a. HCl/MeOH mediated ...
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Aust. J. Chem. 2012, 65, 1262–1270 http://dx.doi.org/10.1071/CH12062

Regioselective Addition of 1,3-Dicarbonyl Dianions to Carbonyl Compounds: One Pot Lactonization and Ketalization of d-Hydroxy-b-keto Esters to Protected Pyrone Derivatives Manas K. Ghorai,A,B Sandipan Halder,A and Sauvik SamantaA A B

Department of Chemistry, Indian Institute of Technology, Kanpur 208016, India. Corresponding author. Email: [email protected]

A simple and efficient strategy for the synthesis of 6-substituted-2-pyrone derivatives, by BF3OEt2 mediated one pot cyclization and keto-protection of d-hydroxy-b-keto esters, obtained via regioselective addition of 1,3-dicarbonyl dianion of ethyl acetoacetate to aldehydes and ketones is described. Manuscript received: 1 February 2012. Manuscript accepted: 16 February 2012. Published online: 2 May 2012.

Introduction Di- and tetrahydropyrones are abundant in many naturally occurring compounds with significant medicinal and biological activities.[1] Furthermore, this ring structure as a representative intermediate has been exploited for several important oxacyclic and other oxygen containing molecules.[2] In particular, kurzilactone,[3] cryptofoline, and obolactone[4] (Fig. 1) are well known in the literature for exhibiting antifungal and cytotoxic activities. Several protocols have been devised for the synthesis of pyrone moieties. These methods include hetero Diels–Alder reactions,[5] metal catalyzed oxidative cyclizations,[6] and ring closing metathesis reactions.[4,7] In this context Light et al. have for the first time used d-hydroxy-b-keto esters, the addition product of a 1,3-dicarbonyl dianion of a b-keto ester with an aldehyde, for the synthesis of pyrone derivatives via a HCl/MeOH mediated cyclization approach.[8] Similarly, Peterson and co-workers have also reported a p-toluenesulfonic acid (PTSA) catalyzed cyclization approach to afford

dihydro-4H-pyran-4-ones.[9a] Dieter et al. have used an acid catalyzed cyclization of vinylogous thiol esters for the synthesis of a-pyrones,[9b] but these methods have limitations in terms of the yield of the addition product as well as formation of the dehydrated product in the cyclization step. Langer et al. have also described a FeCl3 catalyzed cyclization approach for the synthesis of 6-aryl substituted 2,3-dihydro-4H-pyran-4-ones from d-hydroxy-b-diketones.[9c] Hence, development of a suitable procedure for the synthesis of pyrones in higher yields, with control over dehydration processes, is necessary for further functionalization of the pyrone ring. In this context Ley et al. have reported an interesting strategy involving a tandem cyclization of propargylic carbonyl compounds to the corresponding dithiol protected pyrone derivatives.[10] In another approach the reactivity of 1,3-dicarbonyl dianion has been prudently exploited for the synthesis of a variety of heterocyclic scaffolds. Several research groups have made

O

O O

OH

O

O

Kurzilactone 1

OH

OH

(⫹)-Cryptofoline O

O O

O

H

Obolactone 1 Fig. 1. Some dihydropyrone containing natural products.

Journal compilation Ó CSIRO 2012

www.publish.csiro.au/journals/ajc

Oxacycles Pyrones

remarkable efforts in this particular field for the development of newer synthetic routes.[11,12] In this perspective Langer and co-workers have made significant contribution towards the synthesis of a number of heterocyclic frameworks through the utilization of the 1,3-dicarbonyl dianion.[13] Previously we have reported the synthesis of 2-substituted piperidines and diastereopure 2,4-disubstituted azetidine derivatives from d-aminob-keto esters obtained via the regioselective addition of 1,3-dicarbonyl dianion of ethyl acetoacetate to N-tosyl aldimines.[14] In continuation of our research in enolate[15] and dianion chemistry, we anticipated that six membered oxa-cycles could easily be made through a similar strategy using different carbonyl electrophiles. The addition of the dianion generated from ethyl acetoacetate to carbonyl electrophiles would lead to the formation of d-hydroxy-b-keto esters, which could be further converted to 2-substituted pyrone derivatives upon protection of the ketone group followed by cyclization. To our gratification we have successfully developed a Lewis acid (BF3OEt2) catalyzed one pot lactonization-ketalization strategy to furnish 6-substituted-4-keto protected pyrone derivatives in good yield, though alternate cyclization methods were reported earlier.[16] Results and Discussion Our study began with the generation of the dianion 2 from ethyl acetoacetate by treatment with LDA (2.0 equiv.) at 508C in THF followed by reaction with benzaldehyde to afford the corresponding d-hydroxy-b-keto ester 4a in 98 % yield (Table 1, entry 1). The strategy was generalized for other aldehydes and further extended to different ketones. In all cases the reactions proceeded smoothly with excellent yields of the products (Table 1). We have extended this protocol towards the synthesis of a non-racemic addition product 4k; for this purpose chiral Garner’s aldehyde was introduced as an electrophile. After the reaction the addition product was obtained as a mixture diastereomers (40 : 1) which were separated after protection of the –OH functionality as a tert-butyldimethylsilyl (TBDMS) ether (Table 1, entry 11). In the next step, attempted protection of the keto functionality in the addition product 4a was made by treatment with ethanediol in the presence of PTSA; unfortunately, the product decomposed under the harsh reaction conditions. As an alternative, we tried a milder reaction where the substrate was treated with ethylene glycol in the presence of a catalytic amount of BF3OEt2 in CH2Cl2 at 08C to room temperature for 18–20 h.[17] To our great delight, the cyclized 2-pyrone product 5a was obtained with protected ketone functionality in the same pot with good yield (Table 2, entry 1). This protocol was further generalized for other d-hydroxy-b-keto esters 4b –j and the result is shown in Table 2. Addition products 4i and 4j underwent lactonization without further keto protection under the same reaction conditions, and the corresponding 4-ketolactones 5i and 5j were obtained (Table 2, entry 9 and entry 10) in good yields. Crystal structures of 5b, 5d, and 5e as representative examples are shown in Fig. 2. Conclusion In conclusion we have developed a simple strategy for the synthesis of 6-substituted, 4-keto protected, 2-pyrone derivatives via a Lewis acid-catalyzed cyclization of d-hydroxy-bketo ester, obtained by regioselective addition of 1,3-dicarbonyl dianion to aldehydes and ketones. The asymmetric version of

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this work and synthesis of bioactive pyrone molecules using this approach is underway. Experimental General Procedure for the Synthesis of d-Hydroxy-b-keto Ester (4a–k) To a solution of diisopropylamine (0.66 mL, 4.7 mmol) in 1.5 mL of dry THF was added n-BuLi (2.94 mL, 4.7 mmol) [1.6 M solution in hexane] at 08C and stirred for 30 min. The solution changed to light yellow, where it was cooled to 508C and ethyl acetoacetate (0.3 mL, 2.35 mmol) was addedand stirred for a further 1 h to generate the dianion. Aldehydes or ketones (0.94 mmol) in 0.5 mL of THF were added to the reaction mixture and the stirring was continued for an additional 3–4 h at the same temperature. After completion of the reaction as monitored by TLC, the reaction mixture was quenched with saturated aqueous ammonium chloride. The organic and the aqueous layers were separated, and the aqueous layer was extracted with ethyl acetate (3  5 mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude reaction mixture was purified by flash column chromatography on silica gel (230–400 mesh) using 10 % ethyl acetate in petroleum ether to obtain pure d-hydroxy-b-keto ester 4a–j. Ethyl 5-Hydroxy-3-oxo-5-phenylpentanoate (4a) The general procedure described above was followed to afford 4a (218.2 mg, 98 % yield) as a light yellow liquid, Rf 0.33 (20 % ethyl acetate in petroleum ether); IR nmax (neat, cm1) 3473, 3063, 3031, 2982, 2932, 1740, 1713, 1650, 1494, 1453, 1408, 1368, 1319, 1267, 1193, 1156, 1095, 1030, 941, 853, 803, 756, 701; 1H NMR (500 MHz, CDCl3) d 1.26 (t, 3H, J ¼ 7.1 Hz), 2.86–3.05 (m, 2H), 3.47 (s, 2H), 4.18 (q, 2H, J ¼ 7.1 Hz), 5.18 (dd, 1H, J ¼ 3.1, 9.3 Hz), 7.27–7.37 (m, 5H); 13 C NMR (125 MHz, CDCl3) d 14.1, 49.9, 51.6, 61.5, 69.8, 125.6, 127.8, 128.6, 142.5, 166.8, 202.9. Ethyl 5-(2-Bromophenyl)-5-hydroxy-3oxopentanoate (4b) The general procedure described above was followed to afford 4b (207 mg, 76 % yield) as a colourless liquid, Rf 0.35 (20 % ethyl acetate in petroleum ether); IR nmax (neat, cm1) 3440, 3054, 3031, 2967, 2932, 1735, 1705, 1647, 1494, 1453, 1398, 1368, 1267, 1193, 1163, 1030, 964, 850, 803, 759, 701, 577, 544; 1H NMR (400 MHz, CDCl3) d 1.27 (t, 3H, J ¼ 6.8 Hz), 2.73–2.82 (m, 1H), 3.09 (dd, 1H, J ¼ 2.0, 17.6 Hz), 3.49 (s, 2H), 4.19 (q, 2H, J ¼ 6.8 Hz), 5.48 (dd, 1H, J ¼ 2.0, 9.8 Hz), 7.10–7.15 (m, 1H), 7.30–7.35 (m, 1H), 7.49 (d, 1H, J ¼ 7.8 Hz), 7.58–7.62 (m, 1H)13C NMR (100 MHz, CDCl3) d 14.1, 49.7, 49.8, 61.6, 68.7, 121.2, 127.3, 127.9, 129.1, 132.6, 141.4, 166.7, 202.7. Ethyl 5-(3-Bromophenyl)-5-hydroxy-3oxopentanoate (4c) The general procedure described above was followed to afford 4c (218 mg, 80 % yield) as a light yellow liquid, Rf 0.36 (20 % ethyl acetate in petroleum ether); IR nmax (neat, cm1) 3454, 2981, 2926, 1740, 1713, 1650, 1596, 1570, 1473, 1409, 1369, 1317, 1260, 1191, 1095, 1070, 1028, 884, 785, 695; 1 H NMR (400 MHz, CDCl3) d 1.22 (t, 3H, J ¼ 7.3 Hz) 2.82–2.94 (m, 2H), 3.42 (s, 2H), 4.14 (q, 2H, J ¼ 7.1 Hz), 5.05–5.12 (m, 1H), 7.13–7.22 (m, 2H), 7.35 (d, 1H, J ¼ 7.8 Hz),

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M. K. Ghorai, S. Halder, and S. Samanta

Table 1. Synthesis of d-hydroxy-b-keto esters by regioselective addition of 1,3-dianion of ethyl acetoacetate to aldehydes/ketones

O O

O O

LDA, THF ⫺50⬚C, 1 h

1

OLi

OLi O

R1R2CO (3), THF

O

R1

⫺50⬚C, 3 h

O

OH

R2

2

4 Yield: 75–98 %

Entry

Aldehyde or ketone (3)

Addition product (4)

O 1

O O

3a: R1 ¼ Ph, R2 ¼ H

98

Ph

OH

4a

O

O

Br 2

3b: R ¼ 2-Br-C6H4, R ¼ H 1

Yield [%]A

2

O 76

OH 4b

O

O O

3

3c: R ¼ 3-Br-C6H4, R ¼ H 1

2

Br

80

OH

4c

O

O O

4

3d: R ¼ 4-Cl-C6H4, R ¼ H 1

2

75

OH 4d Cl

O

O O

5

3e: R ¼ 4-CN-C6H4, R ¼ H 1

2

81

OH 4e NC O

6

3f: R1 ¼ Me, R2 ¼ Me

O O

H3C H3C

OH

O

7

3g: R1 ¼ Et, R2 ¼ Me

O O

H3CH2C H3C

OH O

8

88

4f

4g

83

O O

3h: R1 ¼ R2–(CH2)4–

95

OH 4h

(Continued )

Oxacycles Pyrones

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Table 1. (Continued) Entry

Aldehyde or ketone (3)

Addition product (4)

O

Yield [%]A

O O

3i: R1 ¼ R2–(CH2)4–

9

OH

90

4i

O

10

3j: R1 ¼ Ph, R2 ¼ Et

O O

Ph H3CH2C

87

OH 4j

O

O O

O B

11

3k: R1 ⫽

N Boc , R2 ⫽ H

OTBDMS

O N

Boc

57C

4k

A

Yields of isolated products after column chromatographic purification. The –OH group of the addition product was protected as a TBDMS ether and the diastereomers were separated. C Isolated product after two steps; dr 40 : 1 (confirmed by the yield of the isolated diastereomers). B

7.47 (s, 1H); 13C NMR (100 MHz, CDCl3) d 14.0, 49.8, 51.4, 61.6, 69.1, 122.7, 124.3, 128.7, 128.8, 130.1, 130.8, 144.8,1 166.7, 202.6. Ethyl 5-(4-Chlorophenyl)-5-hydroxy-3oxopentanoate (4d) The general procedure described above was followed to afford 4d (190 mg, 75 % yield) as a light yellow liquid, Rf 0.27 (20 % ethyl acetate in petroleum ether); IR nmax (neat, cm1) 3456, 2982, 2929, 1740, 1714, 1651, 1492, 1445, 1408, 1369, 1318, 1241, 1192, 1155, 1091, 1031, 1014, 940, 831, 718; 1 H NMR (500 MHz, CDCl3) d 1.26 (t, 3H, J ¼ 6.3 Hz), 2.85–2.99 (m, 2H), 3.46 (s, 2H), 4.18 (q, 2H, J ¼ 7.4 Hz), 5.14–5.16 (m, 1H), 7.25–7.33 (m, 4H); 13C NMR (125 MHz, CDCl3) d 14.1, 49.8, 51.5, 61.7, 69.2, 127.2, 128.8, 133.5, 141.0, 166.9, 202.9. Ethyl 5-(4-Cyanophenyl)-5-hydroxy-3oxopentanoate (4e) The general procedure described above was followed to afford 4e (199 mg, 81 % yield) as a colourless liquid, Rf 0.27 (20 % ethyl acetate in petroleum ether); IR nmax (neat, cm1) 3441, 2987, 2930, 2906, 2229, 1737, 1713, 1610, 1550, 1508, 1451, 1409, 1375, 1327, 1273, 1240, 1194, 1174, 1137, 1081, 1059, 1019, 951, 849, 826, 733; 1H NMR (400 MHz, CDCl3) d 1.20 (t, 3H, J ¼ 7.1 Hz), 2.86–2.88 (m, 2H), 3.41 (s, 2H), 4.01–4.15 (m, 2H), 5.16–5.19 (m, 1H), 7.40–7.58 (m, 4H); 13 C NMR (100 MHz, CDCl3) d 14.0, 49.7, 51.2, 61.7, 69.1, 112.5, 118.6, 126.7, 132.4, 147.8, 166.6, 202.4. Ethyl 5-Hydroxy-5-methyl-3-oxohexanoate (4f ) The general procedure described above was followed to afford 4f (156 mg, 88 % yield) as a light yellow liquid, Rf 0.36 (20 % ethyl acetate in petroleum ether); IR nmax (neat, cm1)

3516, 2977, 2935, 1742, 1709, 1648, 1467, 1369, 1318, 1238, 1178, 1096, 1031, 985, 938, 910, 854, 810, 779; 1H NMR (400 MHz, CDCl3) d 1.21–1.30 (m, 9H), 2.72 (s, 2H), 3.32 (s, 1H), 3.44 (s, 2H), 4.12–4.21 (m, 2H); 13C NMR (100 MHz, CDCl3) d 14.0, 29.3, 50.5, 53.7, 61.4, 69.7, 166.8, 204.2. Ethyl 5-Hydroxy-5-methyl-3-oxoheptanoate (4g) The general procedure described above was followed to afford 4g (158 mg, 83 % yield) as a light yellow liquid, Rf 0.40 (20 % ethyl acetate in petroleum ether); IR nmax (neat, cm1) 3449, 2929, 1738, 1716, 1668, 1498, 1467, 1408, 1369, 1334, 1270, 1178, 1150, 1091, 1054, 1024, 948, 831, 756, 690; 1 H NMR (400 MHz, CDCl3) d 0.88 (t, 3H, J ¼ 7.3 Hz), 1.16 (s, 3H), 1.24 (t, 3H, J ¼ 6.8 Hz), 1.48–1.58 (m, 2H), 2.69 (q, 2H, J ¼ 17.1 Hz), 3.45 (s, 2H), 4.20 (q, 2H, J ¼ 7.1 Hz); 13C NMR (100 MHz, CDCl3) d 8.1, 14.1, 25.3, 26.1, 34.6, 44.2, 48.5, 51.7, 81.5, 166.9, 200.8. Ethyl 4-(1-Hydroxycyclopentyl)-3-oxobutanoate (4h) The general procedure described above was followed to afford 4h (191 mg, 95 % yield) as a light yellow liquid, Rf 0.48 (20 % ethyl acetate in petroleum ether); IR nmax (neat, cm1) 3523, 2962, 2874, 1741, 1710, 1647, 1369, 1320, 1239, 1184, 1095, 1029, 954, 856; 1H NMR (400 MHz, CDCl3) d 1.26 (t, 3H, J ¼ 7.1 Hz), 1.48–1.49 (m, 2H), 1.58–1.61 (m, 2H), 1.78–1.83 (m, 4H), 2.85 (s, 2H), 3.44 (s, 2H), 4.18 (q, 2H, J ¼ 7.1 Hz); 13C NMR (100 MHz, CDCl3) d 14.7, 21.5, 36.3, 50.7, 52.5, 62.0, 70.6, 167.1, 202.4. Ethyl 4-(1-Hydroxycyclohexyl)-3-oxobutanoate (4i) The general procedure described above was followed to afford 4i (193 mg, 90 % yield) as a light yellow liquid, Rf 0.43 (20 % ethyl acetate in petroleum ether); IR nmax (neat, cm1)

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M. K. Ghorai, S. Halder, and S. Samanta

Table 2. BF3.OEt2 catalyzed cyclization of d-hydroxy-b-keto esters to synthesize 6-substituted-4-protected-2-pyrones

O

O

1

R

2

R

Entry

OH

O

OH 4

O

BF3·OEt2,

OH CH2Cl2, 0⬚C to rt 18 to 20 h

O

Yield: up to 65 %

R1 R

2

O

O 5

O 1

Yield [%]A

Cyclized product (5)

4

4a: R1 ¼ Ph, R2 ¼ H

O

Ph

O 5a

55

O

O

O

Br 2

4b: R1 ¼ 2-Br-C6H4, R2 ¼ H

O

52

O

5b

O 3

4c: R1 ¼ 3-Br-C6H4, R2 ¼ H

O

Br

O 5c

O

O

4

4d: R1 ¼ 4-Cl-C6H4, R2 ¼ H

65

O

O 5d

O

62

O

58

Cl

O

5

4e: R1 ¼ 4-CN-C6H4, R2 ¼ H

O 5e

NC

O 6

4f: R1 ¼ Me, R2 ¼ Me

O

H3C H3C

O

O

58

O

5f

O 7

4g: R1 ¼ Et, R2 ¼ Me

H3CH2C H3C

O

O

O

56

5g

(Continued )

Oxacycles Pyrones

1267

Table 2. (Continued) Entry

O

O

4h: R1 ¼ R2 ¼ –(CH2)4–

8

Yield [%]A

Cyclized product (5)

4

O

55

O

5h O

4i: R1 ¼ R2 ¼ –(CH2)5–

9B

O

60

O

5i O Ph H3CH2C

4j: R1 ¼ Ph, R2 ¼ Et

10B

O

63

O

5j

A

Yields of isolated products after column chromatographic purification. The product was obtained as unprotected 4-keto lactone.

B

Br O C H

O N C H

Cl O C H

5b

5d

5e

CCDC No. 864222

CCDC No. 864223

CCDC No. 864224

Fig. 2. X-ray crystal structures of 5b, 5d, and 5e.

3519, 2932, 2858, 1742, 1707, 1647, 1447, 1407, 1368, 1319, 1239, 1170, 1097, 1030, 987, 965, 853; 1H NMR (400 MHz, CDCl3) d 1.20–1.58 (m, 13H), 2.64 (s, 2H), 3.40 (s, 2H), 4.14 (q, 2H, J ¼ 6.9 Hz); 13C NMR (100 MHz, CDCl3) d 14.0, 21.1, 25.6, 37.5, 50.9, 52.8, 61.5, 70.8, 166.9, 204.4. Ethyl 5-Hydroxy-3-oxo-5-phenylheptanoate (4j) The general procedure described above was followed to afford 4j (216 mg, 87 % yield) as a light yellow liquid, Rf 0.30 (20 % ethyl acetate in petroleum ether); IR nmax (neat, cm1) 3513, 3060, 3027, 2977, 2967, 2881, 1741, 1708, 1649, 1494, 1463, 1447, 1369, 1317, 1261, 1161, 1095, 1078, 1030, 961, 855, 795, 762, 702; 1H NMR (400 MHz, CDCl3) d 0.68 (t, 3H, J ¼ 7.3 Hz), 1.18 (t, 3H, J ¼ 7.3 Hz), 1.68–1.82 (m, 2H), 2.88–3.28

(m, 2H), 3.24 (s, 2H), 3.95 (s, 1H), 4.09 (q, 2H, J ¼ 7.3 Hz), 7.14–7.31 (m, 5H); 13C NMR (100 MHz, CDCl3) d 7.6, 14.0, 35.8, 47.2, 50.8, 52.5, 61.5, 125.3, 126.7, 128.0, 166.6, 204.3. Tert-butyl-4-(1-(tert-butyldimethylsilyloxy)-5ethoxy-3,5-dioxopentyl)-2,2-dimethyloxazolidine3-carboxylate (4k) The general procedure described above was followed to afford tert-butyl 4-(5-ethoxy-1-hydroxy-3,5-dioxopentyl)-2,2dimethyloxazolidine-3-carboxylate. The addition product (0.60 mmol) was dissolved in a mixture of pyridine and dichloromethane (1 : 2) and cooled to 08C before addition of t-butyldimethylsilyl trifluoromethanesulfonate (TBDMSOTf). The reaction mixture was warmed to room temperature and

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stirred for an additional 12 h. After completion of the reaction as monitored by TLC, the reaction mixture was quenched with saturated aqueous ammonium chloride. The organic and the aqueous layers were separated, and the aqueous layer was extracted with dichloromethane (3  5 mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude reaction mixture was purified by flash column chromatography on silica gel (230–400 mesh) using 5 % ethyl acetate in petroleum ether to obtain pure 4k (103 mg, 57 % isolated yield of the major diastereomer, diastereomeric ratio 40 : 1) as a light yellow liquid, Rf 0.32 (5 % ethyl acetate in petroleum ether); 1 [a]25 D ¼ 21.4 (c 0.12 in CHCl3); IR nmax (neat, cm ) 3373, 2927, 2856, 1746, 1698, 1652, 1463, 1369, 1317, 1254, 1172, 1096, 1054, 1019, 837, 776; 1H NMR (500 MHz, CDCl3) d 0.02–0.14 (m, 6H), 0.83–0.97 (m, 9H), 1.26 (t, 3H, J ¼ 7.2 Hz), 1.43–1.63 (m, 17H), 2.71–2.76 (m, 1H) 3.44 (s, 2H), 3.81–3.91 (m, 1H), 4.01–4.02 (m, 2H), 4.14–4.20 (m, 2H); 13C NMR (100 MHz, CDCl3) d 4.4, 14.0, 17.9, 22.9, 25.6, 27.0, 28.4, 29.3, 31.9, 37.0, 49.6, 64.1, 80.3, 166.9, 200.2; HRMS (ESI) calcd for C23H44NO7Si (MþHþ): 474.2887, found 474.2885. General Procedure for the Synthesis of Protected Pyrone Derivatives from d-Hydroxy-b-keto Ester (5a–j) The addition product 4a–j (0.42 mmol) was dissolved in 2.0 mL dichloromethane and cooled to 08C before addition of 1,2ethanediol (0.18 mL, 3.36 mmol) and BF3OEt2 (0.03 mL, 0.21 mmol) (diluted in 0.5 mL dichloromethane and cooled to 08C) . The reaction mixture was warmed to room temperature and stirred for 18–20 h. After completion of the reaction, monitored by TLC, the reaction mixture was quenched with cold water. The organic and aqueous layers were separated, and the aqueous layer was extracted with dichloromethane (3  5 mL). The combined organic extract was washed with brine and dried over anhydrous sodium sulfate. After filtration and removal of the solvent under reduced pressure, the crude reaction mixture was purified by flash column chromatography on silica gel (230–400 mesh) using 20 % ethyl acetate in petroleum ether to obtain pure 5a–j. 9-Phenyl-1,4,8-trioxaspiro[4.5]decan-7-one (5a) The general procedure described above was followed to afford 5a (55 mg, 55 % yield) as a colourless thick liquid, Rf 0.51 (40 % ethyl acetate in petroleum ether); IR nmax (neat, cm1) 3064, 3034, 2976, 2927, 2894, 1743, 1614, 1498, 1477, 1455, 1343, 1254, 1234, 1207, 1127, 1082, 1047, 1011, 979, 948, 842, 723; 1H NMR (400 MHz, CDCl3) d 2.06–2.21 (m, 2H), 2.75–2.90 (m, 2H), 3.90–4.02 (m, 4H), 5.39 (dd, 1H, J ¼ 3.4, 11.7 Hz), 7.27–7.38 (m, 5H); 13C NMR (100 MHz, CDCl3) d 41.3, 64.8, 64.9, 78.3, 105.5, 125.9, 128.6, 128.7, 138.5, 168.9; HRMS (ESI) calcd for C13H15O4 (MþHþ): 235.0970, found: 235.0970. 9-(2-Bromophenyl)-1,4,8-trioxaspiro[4.5]decan7-one (5b) The general procedure described above was followed to afford 5b (68 mg, 52 % yield) as a light yellow solid, mp 116– 1188C; Rf 0.48 (40 % ethyl acetate in petroleum ether); IR nmax (KBr, cm1) 3060, 2956, 2884, 1740, 1618, 1490, 1456, 1432, 1341, 1234, 1210, 1133, 1079, 1034, 1011, 980, 932, 840, 715; 1 H NMR (400 MHz, CDCl3) d 1.81–1.88 (m, 1H), 2.38–2.43

M. K. Ghorai, S. Halder, and S. Samanta

(m, 1H), 2.78–2.92 (m, 2H), 3.93–4.09 (m, 4H), 5.74 (dd, 1H, J ¼ 3.2, 12.0 Hz), 7.11–7.15 (m, 1H), 7.29–7.33 (m, 1H), 7.45– 7.49 (m, 2H); 13C NMR (100 MHz, CDCl3) d 39.7, 41.4, 64.9, 105.4, 121.0, 127.4, 128.0, 129.7, 132.9, 137.9, 168.8; HRMS (ESI) calcd for C13H14BrO4 (MþHþ): 313.0075, found: 313.0070. 9-(3-Bromophenyl)-1,4,8-trioxaspiro[4.5]decan7-one (5c) The general procedure described above was followed to afford 5c (85 mg, 65 % yield) as colourless thick liquid, Rf 0.50 (40 % ethyl acetate in petroleum ether); IR nmax (neat, cm1) 3064, 2924, 1745, 1620, 1597, 1572, 1476, 1431, 1367, 1340, 1253, 1230, 1126, 1097, 1075, 1050, 1013, 982, 948, 861, 827, 786, 731; 1H NMR (400 MHz, CDCl3) d 2.0–2.20 (m, 2H), 2.73–2.88 (m, 2H), 3.89–4.04 (m, 4H), 5.36 (dd, 1H, J ¼ 3.2, 12.2 Hz), 7.17–7.25 (m, 2H), 7.39–7.52 (m, 2H); 13C NMR (100 MHz, CDCl3) d 41.4, 64.9, 65.0, 105.4, 122.8, 124.5, 129.1, 130.3, 131.7, 140.9, 168.6; HRMS (ESI) calcd for C13H14BrO4Na (MþNaþ): 334.9894, found: 334.9893. 9-(4-Chlorophenyl)-1,4,8-trioxaspiro[4.5]decan7-one (5d) The general procedure described above was followed to afford 5d (70 mg, 62 % yield) as a light yellow solid, mp 78– 828C; Rf 0.48 (40 % ethyl acetate in petroleum ether); IR nmax (KBr, cm1) 2911, 1746, 1626, 1494, 1416, 1382, 1344, 1289, 1271, 1245, 1107, 1088, 1077, 1047, 1012, 966, 948, 886, 846, 824, 749; 1H NMR (500 MHz, CDCl3) d 2.0–2.20 (m, 2H), 2.60– 2.90 (m, 2H), 3.90–4.01 (m, 4H), 5.37 (dd, 1H, J ¼ 3.4, 12.0 Hz), 7.23–7.31 (m, 4H); 13C NMR (125 MHz, CDCl3) d 42.0, 65.6, 65.7, 78.2, 106.1, 128.0, 129.8, 135.1, 135.7, 169.4; HRMS (ESI) calcd for C13H14ClO4 (MþHþ): 269.0580, found: 269.0587. 4-(9-Oxo-1,4,8-trioxaspiro[4.5]decan-7-yl) benzonitrile (5e) The general procedure described above was followed to afford 5e (63 mg, 58 % yield) as a white solid, mp 83–858C; Rf 0.40 (40 % ethyl acetate in petroleum ether); IR nmax (KBr, cm1) 3441, 2906, 2235, 1731, 1631, 1551, 1467, 1422, 1379, 1343, 1270, 1254, 1233, 1208, 1149, 1108, 1073, 1043, 1011, 979, 948, 902, 851, 819, 734; 1H NMR (500 MHz, CDCl3) d 2.02–2.10 (m, 1H), 2.21–2.26 (m, 1H), 2.78–2.95 (m, 2H), 3.94–4.20 (m, 4H), 5.49 (dd, 1H, J ¼ 2.9, 11.9 Hz), 7.48 (d, 2H, J ¼ 8.6 Hz), 7.67 (d, 2H, J ¼ 8.3 Hz); 13C NMR (125 MHz, CDCl3) d 41.2, 41.3, 64.9, 65.0, 76.7, 105.2, 112.4, 118.3, 126.5, 135.5, 143.8, 168.3; HRMS (ESI) calcd for C14H13NO4Na (MþNaþ): 282.0742, found: 282.0743. 9,9-Dimethyl-1,4,8-trioxaspiro[4.5]decan-7-one (5f ) The general procedure described above was followed to afford 5f (45 mg, 58 % yield) as a colourless liquid, Rf 0.34 (40 % ethyl acetate in petroleum ether); IR nmax (neat, cm1) 2980, 2933, 1733, 1703, 1626, 1446, 1407, 1380, 1360, 1284, 1232, 1177, 1113, 1089, 1032, 1016, 999, 978, 949, 932, 872, 811, 794; 1H NMR (400MHz, CDCl3) d 1.42 (s, 6H), 1.96 (s, 2H), 2.68 (s, 2H), 3.85–3.95 (m, 4H); 13C NMR (100 MHz, CDCl3) d 29.6, 40.6, 43.3, 64.5, 89.9, 105.7, 169.3; HRMS (ESI) calcd for C9H15O4 (MþHþ): 187.0970, found: 187.0979.

Oxacycles Pyrones

1269

9-Ethyl-9-methyl-1,4,8-trioxaspiro[4.5]decan7-one (5g) The general procedure described above was followed to afford 5g (47 mg, 56 % yield) as a colourless liquid, Rf 0.39 (40 % ethyl acetate in petroleum ether); IR nmax (neat, cm1) 2976, 2926, 1733, 1698, 1645, 1462, 1383, 1361, 1327, 1274, 1224, 1164, 1101, 1017, 979, 949, 795; 1H NMR (400MHz, CDCl3) d 0.85–0.97 (m, 5H), 1.38 (s, 3H), 1.83–2.01 (m, 2H), 2.56–2.69 (m, 2H), 3.87–3.93 (m, 4H); 13C NMR (100 MHz, CDCl3) d 8.1, 26.4, 35.2, 40.8, 44.148.4, 64.4, 83.3, 105.8, 169.3; HRMS (ESI) calcd for C10H16O4Na (MþNa): 223.0946, found: 223.0948. 1,4,8-Trioxadispiro[4.3.4.1]tetradecane-7-one (5h)[18] The general procedure described above was followed to afford 5h (49 mg, 55 % yield) as a light yellow liquid, Rf 0.38 (40 % ethyl acetate in petroleum ether); IR nmax (neat, cm1) 2987, 2964, 1740, 1636, 1542, 1472, 1415, 1383, 1334, 1278, 1232, 1208, 1172, 1122, 1078, 1048, 1028, 988, 972, 922, 870, 832, 785, 634; 1H NMR (400MHz, CDCl3) d 1.63–2.11 (m, 10H), 2.74 (s, 3H), 3.91–3.96 (m, 4H); 13C NMR (100 MHz, CDCl3) d 23.6, 40.0, 41.2, 41.8, 64.6, 90.9, 169.4; HRMS (ESI) calcd for C11H17O4 (MþHþ): 213.1127, found: 213.1126. 1-Oxaspiro[5.5]undecane-2,4-dione (5i) The general procedure described above was followed to afford 5i (46 mg, 60 % yield) as a light yellow liquid, Rf 0.51 (40 % ethyl acetate in petroleum ether); IR nmax (neat, cm1) 2956, 1735, 1636, 1446, 1407, 1382, 1355, 1284, 1232, 1217, 1175, 1120, 1089, 1024, 1016, 999, 978, 966, 954, 872, 832, 770, 641; 1H NMR (400MHz, CDCl3) d 1.19–1.82 (m, 10H), 2.60 (s, 2H), 3.35 (s, 2H); 13C NMR (100 MHz, CDCl3) d 21.4, 24.6, 36.8, 44.4, 49.4, 80.4, 167.3, 200.8; HRMS (ESI) calcd for C10H15O3 (MþHþ): 183.1021, found: 183.1027. 6-Ethyl-6-phenyldihydro-2H-pyran-2,4(3H)-dione (5j) The general procedure described above was followed to afford 5j (58 mg, 63 % yield) as a light yellow liquid, Rf 0.39 (40 % ethyl acetate in petroleum ether); IR nmax (neat, cm1) 2971, 2925, 2854, 1727, 1663, 1618, 1494, 1450, 1410, 1332, 1260, 1226, 1174, 1090, 1018, 972, 894, 829, 804, 760, 701; 1 H NMR (400MHz, CDCl3) d 0.80–0.84 (m, 3H), 1.96–1.99 (m, 2H), 1.83–2.01 (m, 2H), 2.79–2.89 (m, 2H), 3.16–3. 31 (m, 2H), 7.22–7.33 (m, 5H); 13C NMR (100 MHz, CDCl3) d 8.4, 35.3, 36.3, 45.9, 47.4, 124.3, 125.9, 128.5, 130.1, 167.8; HRMS (ESI) calcd for C13H13O3 (MHþ): 217.0865, found: 217.0867.

[2]

Acknowledgements MKG is grateful to IIT-Kanpur and DST, India for financial support. SH and SS are thankful to UGC and CSIR, India, respectively, for their research fellowships.

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