Chapter-3: Eco-friendly Wacker process

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3.1 Introduction Palladium (Pd) is an element form platinum group metals (PGMs). Palladium is used in all fields of sciences along with chemical science. Common oxidation states of palladium are 0, +1, +2 and +4. Numbers of reactions are reported in which palladium is used. Palladium catalyzed reaction such as Wacker oxidation,1 Heck reaction,2 Suzuki coupling reaction,3 Sonogashira coupling reaction,4 Hartwig Cross Coupling Reaction5 and Saegusa oxidation6 etc. have gained a lot of importance and popularity in the area of synthetic organic chemistry over a period of time. All these reactions proceed through π complexes. In all these reactions Pd was used in the form of Pd(I/II)7,8,9 .It was shown that Pd can be used as a catalyst in the Pd(0)8,10 form in Heck reaction, Suzuki reaction and Sonogashira coupling reaction. However, in all of the Wacker oxidations reported so far, Pd was used in the form of Pd(II) state. There are no reports of effecting Wacker oxidation using Pd (0) species. Phillips in 1894 oxidised ethylene to acetaldehyde by Pd (II) chloride solutions in acidic medium. During the reaction palladium forms a complex with ethylene, is reduced to Pdo. Latter on Smidt and co-workers (1959) used cupric chloride to regenerate the Pdo catalyst. Smidt’s process was applicable to large scale production due 11 to the final recycling of CuCl back to Cu(II)Cl2 by air. The simplified mechanism of

Wacker Oxidation with PdCl2 as the catalyst, and catalytic amounts of copper chloride are used with oxygen to regenerate the active Pd(II) species is shown in Figure 1.

Figure 1

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Palladium decomposition and chlorinated by products limit the use of the Wacker oxidation. Many modifications have been developed allowing for oxidation of more complex targets, but most still utilize the addition of a copper cocatalyst.11 Copper additives severely limit the use of ligands with Pd. Ligand modulation of Pd catalysis has proven to be vital in the development of more effective and asymmetric catalysts for the mechanistically related aerobic alcohol oxidation.12 Conventional Wacker oxidation using homogeneous Pd catalysts often leads to difficulties in isolation of the products, separation of the catalysts from the reaction mixture, and recyclability of the catalysts. Therefore, much effort has been devoted to development of highly efficient Wacker oxidation by heterogeneous catalysts.13,14 Various Pd complex catalysts immobilized on organic or inorganic supports have been reported15,16 for this purpose, but these catalyst systems often have drawbacks such as low catalytic activity, low yield of product and sever dependence of success of the reaction on the structural substituent’s. Copper Chloride is a corrosive chemical cited by DOT, DEP and EPA. It may damage the liver and kidneys. Copper Chloride can affect skin and eye. Breathing of copper chloride can irritate throat, lungs and stomach causing salivation, nausea, vomiting and diarrhea. Prolonged exposure can cause hole in the bone dividing the inner nose.17 So we were interested in developing a catalytic system for the Wacker oxidation that would allow to use oxidants other than copper additives.

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3.1.1 Literature review Tsuji18 et al (1975): Wacker oxidation of higher terminal alkenes affords methyl ketones rather than the corresponding aldehyde barring a few exceptions (fig. 2).

Figure 2

This reaction appears to involve a Markonikov hydration of the complexed double bond followed by oxidation resulting in a one step conversion to methyl ketones. Thus the terminal olefins can be regarded as masked methyl ketones. Wacker oxidation tolerates various19 types of functional groups such as aldehyde, ketone ester, nitrile etc. Application of this type of oxidation to substituted olefins has evolved as synthetic useful tool.

Michel Roussel20 et al. (1980) added 30% hydrogen peroxide to a solution of palladium(II) acetate in acetic acid or tert-butyl alcohol at room temperature resulted in an immediate decomposition with evolution of molecular oxygen. When this addition was carried out in the presence of 1-octene, no decomposition was observed and color changes from yellow-orange to deep orange. GLC analysis showed the formation of 2- octanone as the major product (fig. 3).

Figure 3

Bodo Betzemeier21 developed a methodology to perform the Wacker oxidation of various polyfunctional olefins under mild conditions leading to the corresponding methyl ketones in the presence of the palladium catalyst in a biphasic solvent system of bromoperfluorooctane and benzene using t-butylhydroperoxide (1.5 - 3.5 equiv) as oxidation agent (fig. 4).

Figure 4

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Timothy et al.22 developed oxidation of terminal olefin to aldehyde and ketone respectively. In this reaction the use of LiCl and CuCl reduced the regioselectivity. The selective formation of aldehyde was 30%, while that of ketone was 70%. This methodology is applied for different condition and mole percentage of co-catalyst was studied (fig. 5).

Figure 5

Eric Monflier23 et al developed very useful and efficient Wacker oxidation of higher α- olefins by using a multicomponent catalytic system, i.e. PdSO4/H9PV6Mo6O40/CuSO4 and per (2,6-di-o-methyl)-β-cyclodextrin to obtained the corresponding 2-ketones in high yields (>90 %) (fig. 6).

Figure 6

24 Hari Babu Mereyala et al.(1997): A study of Pd(II)Cl2/CuCl catalysed Wacker reaction for the deprotection of prop-2-enyl and prop-1-enyl ethers was reported. In this

Pd(II)Cl2 (1 mole equivalent)/CuCl/DMF-H2O/O2/2h catalyzed oxidation of various prop-2-enyl ethers was reported to result in the formation of Wacker ketones (12–51%), hydrolysis products (12–43%) and η2-vinyl complexes of palladium chloride (52–94%) respectively. The corresponding prop-1-enyl ethers under similar conditions react with a catalytic amount of Pd(II)Cl2 (0.2 mole equivalent) rapidly (15–20 min.) to give exclusively hydroxy compounds respectively in good yields (75–97%)(fig. 7).

Figure 7

Amos B. Smith et al.25 made modification in the Wacker oxidation of terminal olefins to methyl ketones using substoichiometric amounts of Cu(OAc)2 as a redox shuttle reagent. The modified procedure is generally high yielding despite reduced levels of copper salt and convenient. Importantly, in a problematic case, the conditions

182 suppressed acidic hydrolysis during oxidation of substrate containing an acetonide (fig. 8).

Figure 8

Standard Wacker oxidation provides 57% yield. Modified procedure gives 86% yield with 2 eq. Cu(OAc)2 and 84% yield with 0.2 equivalence of Cu(OAc)2 without acetonide hydrolysis.

Arata Kishi26et al. (2000) Wacker-type oxidation of cyclopentene to cyclopentanone under dioxygen atmosphere was successfully achieved by the use of Pd(OAc)2 and molybdovanadophosphate supported on activated carbon, [Pd(OAc)2–NPMoV/C], catalyst49. Thus, the reaction of cyclopentene under O2 (1 atm) in aqueous acetonitrile acidified by CH3SO3H in the presence of [Pd(OAc)2–NPMoV/C] at 50°C produced cyclopentanone in 85% yield along with a small amount of cyclopentenone (1%) (fig. 9).

Figure 9

Marisa S. Melgo27 et.al (2004) The Wacker oxidation of cyclohexene to cyclohexanone, using the chloride ion-free catalytic system Pd(NO3)2/CuSO4/H3PMo12O40, was investigated at different air pressures, temperatures, and catalyst concentrations. The results show that this system is very efficient and highly selective. After 1 h of reaction at 80 °C and an air pressure of 50 bar, a conversion of 80%, with a turnover frequency of 260 h−1, and a selectivity of more than 99% for cyclohexanone was obtained. Using aqueous hydrogen peroxide and no external pressure, the oxidation was more rapid, giving 80% conversion already after 30 min and 95% conversion after 60 min without the formation of any byproducts (fig. 10).

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Figure 10

I.A. Ansari et.al (2005)28

A simple and efficient PdCl2/CuCl catalyzed oxidation of alkenes has been successfully developed using a mixture of water and the ionic liquid [bmim][BF4] as solvent. Starting from various types of terminal olefins, the corresponding ketones have been prepared under mild reaction conditions and obtained in good to excellent yields after a simple extraction with diethyl ether. Furthermore, it was possible to recycle and reuse the ionic liquid and the catalytic system (fig. 11).

Figure 11

Takato Mitsudome et.al (2006)29 In a recent report palladium-montmorillonite was proven to be highly efficient for the Wacker oxidation of terminal olefins to the corresponding methyl ketones47. The catalyst was reusable while maintaining high activity and selectivity (fig. 12).

Figure 12

Candace N. Cornell et al 30 (2006)

Direct O2-coupled Wacker oxidation by O2 balloon pressure and catalytic amount of catalyst was described. Use of (−)-sparteine as a ligand on Pd prevents olefin isomerization and leads to selective formation of methyl ketones from terminal olefins in good yields. Enantiomerically pure substrates were oxidized without any type of racemisation (fig. 13).

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Figure 13

Brian Michel31et al (2010) Michel targeted the use of ligands on Pd(II) to control oxidative processes. In this regard, he developed tert-butylhydroperoxide (TBHP) mediated Wacker-type oxidation, which was shown to be highly selective for the methyl ketone product in the oxidation of terminal olefins, including protected allylic alcohols and the phthalimide substrates. In this process a bidentate ligand (Quinox) along with TBHP was used. It was believed that TBHP undergoes a syn-oxypalladation mechanism, which allows interaction of the group adjacent to the olefin with the Pd center (fig. 14).

Figure 14

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3.1.2 Present work 3.1.2.1 Objective

Conventional Wacker process with Pd(II) and CuCl2 leads to the formation of substantial amounts of ecologically hazardous chlorinated by-products. Beside this, use of molecular oxygen as a final oxidant presents a significant safety issue.34 Elimination of CuCl2 as co-catalyst and use of Pd(0) would render the Wacker oxidation a completely eco friendly process. Potassium bromate (KBrO3) is an inexpensive, readily available strong oxidizing agent used with different catalysts in various organic reactions as a co-oxidant in stoichiometric quantities.37 Herein we reported Wacker 0 oxidation using Pd /C with KBrO3 as terminal oxidant. Wacker oxidation of terminal olefin was conducted using 10% Pd0/C with potassium bromate as co-oxidant in aqueous THF at reflux temperature and gave corresponding methyl ketone in good yield without any detectable amounts of side products (Table-2). The catalyst recovred can be used for number of cycles without loss in yield. To check the importance of this method we synthesized number of compounds with terminal double bond with different acid/base sensitive functional groups using Wittig-Claisen rearrangement protocol, Barbier method, Grignard reaction etc. This finding makes present Wacker oxidation protocol, a practical, convenient, cheap, and environmentally benign method with the potential application for large-scale preparation of methyl ketones.

3.1.3 Result and Discussion 3.1.3.1 Preparation of terminal olefins The preparation of allyloxymethylene triphenylphosphorane could be achieved from corresponding allyoxitriphenylphosphonium salts. Such phosphonium salt in turn could be prepared from triphenylphosphine and allyl chloromethyl ether (figure-15). The detailed procedure is as described in Chapter-1.

Figure 15

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The IR spectrum of the phosphonium salt showed a weak absorption band at 1632 cm-1 corresponded to the conjugated olefin. The 1HNMR spectrum of this salt showed a doublet at δ 4.39 integrating for two protons with coupling constant 5.1 Hz. This corresponded to the allylic methylene protons. Multiplet at 5.24 with integration for two methylene protons and another multiplet at 5.7 integrating for one methine proton were due to typically monosubstituted olefin. The methylene adjacent to the phosphorus appeared at 5.83. Due to coupling of these protons with phosphorus, the signal was split into doublet with coupling constant 4.6 Hz. Multiplet at 7.8 integrating for fifteen protons corresponded to the protons on the three phenyl rings. Olefinic compounds octane 1, styrene 2, and 4-allylbenzene-1,2-diol 3 (fig. 16) were purchased from Avra Chemicals and other olefinic compounds were synthesized in lab from appropriate starting material with the help of Wittig-Claisen rearrangement and Barbier reaction.

Figure 16

Eugenol 3 (fig. 16) on methylation with DMS and K2CO3 in dry acetone gives 4-allyl- 1,2-dimethoxybenzene 4 in 89% yields. In IR (neat) of compound 4 strong peaks at 1261cm-1 and 1234 cm-1corresponded to ether linkage. Peaks at 1514, 1591, and 1635 corresponded to aromatic double bonds. Peaks observed at 2937 and 833 cm-1 corresponded to terminal double bond. In 1H NMR a doublet at δ 3.35 with coupling constant 6.60 Hz integrating for two protons corresponded to methylene protons adjacent to aromatic ring. Two singlets at 3.86 and 3.87 both of each integrating for three protons corresponded to two methyl protons for two methoxy groups. A multiplets integrating for two protons corresponded to terminal olefin protons. Another multiplet at 5.10 integrating for one proton corresponded to olefin proton adjacent to methylene group. A doublet at 6.70 with coupling constant 7.7 Hz integrating for one proton corresponded to aromatic proton ortho to methoxy group and meta to allyl group. A singlet at 6.73 integrating for one proton corresponded to aromatic proton ortho to both methoxy group and allyl group. A doublet at 6.81 with coupling constant 7.97 Hz integrating for one proton corresponded to aromatic proton meta to methoxy group and ortho to allyl group. In 13C

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NMR spectrum (75MHz, CDCl3), peaks resonated at δ 146.7 and 148.2 corresponded to aromatic carbons. Peaks55.2 and 55.3 corresponded methoxy carbons. These spectral data supports the structure 4. Benzyl alcohol 5 was protected as its allyl ether in presence of NaH and allyl bromide gives ((allyloxy)methyl)benzene 6 in 90 % yields. The IR spectrum of the compound show strong absorption at 1645 cm-1 corresponded to olefin. Strong absorption at 1091, 1076 cm-1 indicates ether linkage. In 1H NMR spectrum, a doublet at 4.04 with coupling constant 1.46 Hz integrating for two protons corresponded to methylene protons adjacent to olefin. A singlet at 4.50 integrating for two protons corresponded to methylene protons adjacent to aromatic ring. A multiplet between 5.17–5.35 integrating for two protons corresponded to terminal olefin protons. Another multiplet resonated between 5.90–6.00 corresponded to olefin proton adjacent to methylene group. A multiplet at 7.34 integrating for five protons corresponded to aromatic protons. In 13C NMR spectrum (75MHz, CDCl3), peaks at 70.72 and 71.71 corresponded to carbons of ether group. Peaks at 134.33 and 137.86 corresponded to olefinic carbons. This spectral date supports the structure 6.

Figure 17 Similarly (2,6-dimethylphenyl)methanol 7 was protected as allyl ether to get 2- ((allyloxy)methyl)-1,3-dimethylbenzene 8.

Figure 18

Esterification of benzoic acid 9 with allyl bromide in presence of H2SO4 gives allyl benzoate 10 in 72 % yields. The reaction was completed in 4h. The IR spectrum of the compound showed strong absorption at 1720 cm-1 corresponded to aromatic ester. A strong absorption peak at 2983 cm-1 was corresponded non aromatic double bond. A doublet at 4.82 corresponded to two protons for methylene protons. A multiplet between 5.25-5.84 integrating for three protons corresponded to olefinic protons. A multiplet at 7.25-8.03 integrating for five protons corresponded to aromatic protons.

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Figure 19

Esterification of 3,5-dinitrobenzoic acid 11 with allyl bromide in presence of

H2SO4 gave allyl 3,5-dinitrobenzoate 12 in 78 % yield. The reaction was completed in 3.5h. The IR spectrum of the compound show strong absorption at 1734.06 cm-1 corresponded to aromatic ester. The peaks observed at 1627 and 923 was attributed to the terminal olefin. A strong absorption band at 1543 cm-1 corresponded to nitro group. In 1HNMR a multiplet at δ 4.89 integrating for two protons corresponded to methylene protons. A multiplet at 5.24-5.45 integrating for two protons corresponded to terminal olefinic protons. A multiplet at 5.96-6.09 integrating for one proton corresponded to terminal olefinic proton. A multiplet at 9.03 integrating for three protons corresponded 13 to aromatic protons. In C NMR (75MHz, CDCl3) peak at 161.84 confirmed the presence of ester functionality. These spectral data supports the structure 12.

Figure 20

Reaction of o-chlorobenzaldehyde 13 with Phosphorane salt gives the expected allyl vinyl ether 14 in 83% yields. The Claisen rearrangement of this allyl vinyl ether 14 was effected by heating a toluene solution of allyl vinyl ether to reflux for 18h at 120oC to give 2-(2-chlorophenyl)pent-4-enal 15 in 93% yield. The crude products were subjected to purification by column chromatography using hexane and ethyl acetate mixture as eluent.

Figure 21

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In the IR spectrum of compound 15, signal observed at 1726.2 cm-1 corresponded to an aldehyde carbonyl. Weak absorption peak at 2920 cm-1 confirmed the presence of the aldehyde carbonyl group. The weak absorption at 1641.3cm-1 was attributed to the terminal olefin and strong absorption at 1041.5 cm-1 confirmed it to be a monosubstituted double bond. In the 1H NMR spectrum, one proton of allylic methylene group appeared as multiplet resonating between δ 2.54-2.58. Another proton of the allylic methylene group appeared as multiplet between 2.82-2.95. Triplet at 4.17 with coupling constant 6.8 Hz integrating for one proton was attributed to the proton α to the aldehyde group. Multiplets between 4.96-5.05 and 5.66-5.80 integrating for two and one protons respectively were typical for monosubstituted olefin. A doublet of doublet appeared at 7.12 with coupling constant 2 Hz and 6.2 Hz integrating for one proton corresponded to aromatic proton α to the methine group. A doublet of doublet appeared at δ 7.42 with coupling constant 2Hz and 6.2Hz integrating for one proton corresponded to aromatic proton α to the chlorine atom. Remaining two aromatic protons appeared as a multiplet between 7.15-7.28. Singlet at 9.68 integrating for one proton corresponded to aldehydic proton. Reaction of o-nitrobenzaldehyde 16 with phosphorane give the expected (E)-1-(2- (allyloxy)vinyl)-2-nitrobenzene 17.

Figure 22

The allyl vinyl ether 17 on Claisen rearrangements in 12 hours gave a 2-(2- nitrophenyl)pent-4-enal 18 in 90% yields. IR spectrum of the compound 18 show a strong absorption peak at 1726.35cm-1 corresponded to an aldehyde carbonyl. Strong peak at 1527.67 cm-1 corresponded to nitro group. Weak absorption peak at 2924 cm-1 confirmed the presence of the aldehyde carbonyl group. The weak absorption at 1641.48 cm-1 was attributed to the unconjugated olefin and strong absorption peak at 1076.32 confirmed it to be a monosubstituted double bond. In the 1H NMR spectrum, one proton of allylic methylene group appeared as multiplet at 2.92. Another proton of the allylic methylene group appeared as multiplet at 2.58. Triplet at 4.29 with coupling constant 7.4 Hz integrating for one proton was attributed to the proton α to the aldehyde group. Multiplets at 5.02 and 5.72 integrating for two and one protons respectively were typical

190 for monosubstituted olefin. A doublet appeared at 7.35 with coupling constant 8 Hz integrating for one proton corresponded to aromatic proton α to the methine group. A doublet appeared at 7.95 with coupling constant 8Hz integrating for one proton corresponded to aromatic proton α to the nitro group. A triplet appeared at 7.45 with coupling constant 7.9 Hz integrating for one proton corresponded to aromatic proton β to the methine group. A triplet appeared at 7.61 with coupling constant 7.94 Hz integrating for one proton corresponded to aromatic proton β to the nitro group. Singlet at 9.76 integrating for one proton corresponded to aldehyde proton. The reaction mixture of veratraldehyde 19 and phosphonium salt was stirred at 0 oC for 5 min. and t-Butoxide was added portion wise. Reaction mixture was stirred for half an hour. After completion of reaction (checked by TLC) it was diluted with water and extracted with ether. Ether layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product obtained was purified by column chromatography using 2% ethyl acetate in hexane as eluent to give (E)-4-(2- (allyloxy)vinyl)-1,2-dimethoxy benzene 20. In the IR spectrum, weak absorption band at 1681.2 cm-1 and 1653.6 cm-1 corresponded to two conjugated olefin groups. Strong absorption band at 812.6 cm-1 confirmed that one of the olefin is terminal olefin. In the 1HNMR spectrum, a singlet at δ 4.2 integrating for six protons indicated the presence of two methoxy groups on the aromatic ring Multiplet at 4.66 with integration for two protons showed presence of allylic methylene group.

Figure 23

Multiplet at δ 5.68 integrating for two protons and multiplete at 6.42, a doublet at 6.6 a doublet at 7.82 each integrating for one proton indicated the presence of five vinylic protons. A multiplet at 7.44 integrating for three protons indicated the presence of trisubstituted benzene ring. A multiplet at δ 5.68 integrating for two protons and a multiplate at 6.22 integrating for one proton corresponded to the monosubstituted olefin. The doublet at 6.62 and 7.82 each integrating for one proton corresponded to proton on enol ether. This spectral data indicated that the expected allyl vinyl ether has formed successfully in 86% yield. The allyl vinyl ethers were obtained as a mixture of E/Z isomers in the ratio of 1:1 approximately, which remain inseparable by normal gravity column chromatography.

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Refluxing a toluene solution of allyl vinyl ether 20 for 10 hours effected the Claisen rearrangement to give pentenal 21 which was further reduced to alcohol and protected as its benzyl ether, 4-(1-(benzyloxy)pent-4-en-2-yl)-1,2-dimethoxybenzene 22. The crude product was subjected to purification by column chromatography (95% yields) using hexane and ethyl acetate mixture as an eluent.

Figure 24 IR spectrum of the pentinal 21, strong absorption peak at 1722 cm-1 corresponded to an aldehyde carbonyl. Weak absorption peak at 2719.3 cm-1 confirmed the presence of the aldehyde carbonyl group. The weak absorption at 1681.2 cm-1 and 918 cm-1 was attributed to the terminal double bond. In the 1H NMR spectrum, allylic methylene group appeared as multiplet at δ 2.79. Multiplet at 3.68 integrating for one proton was attributed to the proton α to the aldehyde group. Singlet at 4.02 integrating for six protons corresponded to the two methoxy groups. Multiplets at 5.30 and 6.00 integrating for two and one protons respectively were typical for terminal olefin. Aromatic protons show multiplet resonated between 6.96-7.88. Doublet at δ 10.24 with coupling constant 2.4 Hz integrating for one proton corresponded to proton from aldehyde functionality. 3,4-dimethoxybenzaldehyde 19 was subjected to Grignard reaction with vinyl magnesium bromide to give 1-(3,4-dimethoxyphenyl)prop-2-en-1-ol 23 which was further protected as its benzyl ether to give 4-(1-(benzyloxy)allyl)-1,2- dimethoxybenzene 24.

Figure 25

Benzaldehyde 25 was treated with allyl bromide in presence of Zn dust to produce 1- phenylbut-3-en-1-ol 26 which was further protected as its benzoyl ether, 1-phenylbut-3- en-1-yl benzoate 27. Similarly aldehyde 28 was subjected to Barbier reaction to produce

192 alcohol 29 and benzyl ether, 6-(benzyloxy)-5-(1-(benzyloxy)but-3-en-1-yl)-2,2- dimethyltetrahydrofuro[2,3-d][1,3]dioxole 30. Aldehyde 28 can be obtained from D- glucose with the help of reported methods.

Figure 26

Figure 27

The tritosylated compound 32 was synthesized from diol 31 which was prepared from D-glucose.

Figure 28

The diol 31 was treated with excess sodium hydride and resulting dialkoxide was treated with 2.5 equivalent of tosyl chloride .The tri-tosylated compound 32 obtained (58% yield) was then reduced, by heating in dimethyl formamide with sodium iodide and zinc at 100 oC for 4h. The expected tosyl compound 33 was obtained in 74% yield. The spectral data of this compound was in accordance with the literature values. (2S,5S)-2-allyl-5-isopropyl-2-methylcyclohexanone 34 was prepared using tetrahydro carvone and allyl bromide in presence of sodium t-butoxide in dry THF at -20 oC. After 1h (TLCcheck) reaction was allowed to attain room temperature and stirred for additional 2h.The reaction was diluted with water and extracted with ether (3 x 20 ml). The combined ether layer was concentrated and purification is carried out using silica

193 gel column chromatography in 1% acetone in hexane as a solvent system gave 64% yield of the pure product. IR spectrum of the product exhibits the strong absorption peaks at 1701 cm-1 corresponded to carbonyl group. The 1H NMR spectrum of the compound show a multiplet resonating between δ 0.86-0.90 integrating for six protons due to the gem dimethyl groups. The remaining methyl group appeared as singlet at 0.99. A multiplate between 1.47-1.66, integrating for five protons probably due to the two methylene protons in the ring and a proton attached to the carbon carrying gem dimethyl group. A proton attached to the isopropyl carrying carbon showed a doublet of doublet between 1.82-1.88 region with the coupling constant of 3.5 Hz and 10.4 Hz. Two protons alpha to the carbonyl group and two allylic protons appeared as multiplet between 2.12- 2.45.Terminal vinylic protons appeared as multiplet between 4.99-5.05 and integrating for two protons. Another multiplate observed between 5.57-5.66 region integrating for one proton was due to the internal vinylic proton. In the 13C NMR spectrum, signal at 19.4, 19.6, 22.1corresponded to the three-methyl groups. The peaks at 24.3, 32.6, 37.9, and 41.4 were due to the two methylene carbons and two trisubstituted carbons. An allylic carbon and carbons alpha to the carbonyl appeared at 42.2 and 45.9. The quaternary carbon appeared at 48.0. Two vinyl carbons showed two signals at 117.9 and 132.8, while the carbonyl carbon appeared at 215.3. Thus the above all data confirms the structure of the compound 34. Compound 34 was reduced to alcohol 35 with the help of sodiumborohydride and alcohol methylated using methyl iodide to give compound 36.

Figure 29 Menthone was allylated with allyl bromide using sodium t-butoxide as a base in THF at –20 oC for 4-5 h. The reaction mixture was diluted with water and extracted with water and extracted in diethyl ether. The ether layer was concentrated and dried over anhydrous sodium sulphate .On chromatographic purification of the crude product using 1% acetone in hexane as solvent system, (3S,6R)-2-allyl-6-isopropyl-3-

194 methylcyclohexanone 37 was obtained in 67% yield. The structure of the product was confirmed by spectral analysis.

In the IR spectrum a strong band due to carbonyl frequency was observed at 1703 cm-1. Peak observed at 1639 cm-1 corresponded to the carbon double bond. The 1HNMR spectrum show two doublets at δ 0.71 and δ 0.90 each showing coupling constant at of 6.8 Hz corresponded to the two methyl groups of the isopropyl group. A doublet at δ 1.04 integrating for three protons showing a coupling constant of 3.3 Hz corresponded to the remaining methyl group of the product. A multiplet between 1.49- 1-80, integrating for four protons corresponded to two methylene groups of the cyclohexene ring. Two protons were observed between 2.04-2.19 corresponded to the two methylene protons. Two allylic protons and one proton alpha to the carbonyl group appeared between 2.30-2.34 as a multiplet, while alpha protons showed a multiplet between the region of 2.52- 2.58. The terminal olefin showed a multiplet between 4.92- 5.06. The internal olefinic protons appeared as multiplet between 5.68-5.88. The 13C NMR of the product 18 show signals at 16.5, 21.9 and 22.6 corresponding to the three methyl groups. Peaks at 28.2, 29.1, 31.5, 34.6, and 47.6 were due to the three methylene and two trisubstituted carbons. Two α-carbons of the carbonyl group appeared at 51.1 and 56.1. The terminal olefinic carbon appeared at 214.3 due to the carbonyl carbon of the product 35. 1,4-dioxaspiro[4.5]decane-2-carbaldehyde 38 under Barbier reaction conditions produces 1-(1,4-dioxaspiro[4.5]decan-2-yl)but-3-en-1-ol 39, which was further protected as its benzyl ether, 2-(1-(benzyloxy)but-3-en-1-yl)-1,4-dioxaspiro[4.5]decane 40 (fig. 30).

Figure 30

195

To apply the Wittig olefination-Claisen rearrangement protocol to the aldehyde 38, it was treated with allyloxymethylenetriphenylphosphorane in dry THF at 50- 55 °C to obtain (E)-2-(2-(allyloxy)vinyl)-1,4-dioxaspiro[4.5]decane 41 in 78% yield. The isomeric mixture of allyl vinyl ether 41 as such was refluxed in xylene to effect the Claisen rearrangement. After Claisen rearrangement we obtained aldehyde which was reduced to alcohol and protected as benzyl ether to give 2-((R)-1-(benzyloxy)pent-4-en- 2-yl)-1,4-dioxaspiro[4.5]decane 42.

Figure 31

IR spectrum of compound 42 showed sharp signals at 1641 and 912 cm-1 for terminal olefin. Absorption bands at 1448 and 737 cm-1 showed presence of aromatic group. Stretching at 1103 cm-1 corresponded to ether linkage. In 1H NMR spectrum multiplet integrating for ten protons between δ 1.39- 1.67 was attributed to methylene protons of cyclohexyl group. Homoallylic methyne proton showed multiplet between δ 1.84- 1.94. Multiplet between δ 2.12- 2.22 was due to one of the allylic methyne protons while remaining allylic methyne proton exhibited multiplet between δ 2.36- 2.44. Doublet of a doublet at δ 3.37 with coupling constants of 9.4 and 6.7 Hz attributed to one of the methylene protons of carbon carrying benzyl ether whereas another doublet of doublet at δ 3.45 with coupling constants of 9.5 and 4.6 Hz was due to remaining methylene proton. One of the methylene protons of dioxolane ring appeared as multiplet between δ 3.66- 3.72. Remaining methylene proton and methyne proton of dioxolane ring together exhibited a multiplet between δ 4.00- 4.11. Singlet for two protons at δ 4.45 was due to benzylic methylene protons. Doublet at δ 5.01 with coupling constant of 8.2 Hz attributed to one of the terminal olefinic protons while another terminal olefinic proton showed doublet at δ 5.04 with coupling constant of 15.4 Hz. Internal proton of olefin appeared as multiplet between δ 5.74- 5.88. A multiplet integrating for five protons at δ 7.25- 7.36 was attributed to aromatic protons of benzyl group. In 13C NMR signals at δ 23.9, 24.0, 25.2, 35.2 and 36.3 attributed to methylene carbons of cyclohexyl group. Homoallylic methyne carbon exhibited signal at δ 32.7 whereas

196 allylic methylene carbon showed peak at δ 42.0. Methylene and methyne carbons of dioxolane ring gave signals at δ 67.9 and 76.7 respectively. Methylene carbon bearing benzyl ether appeared at δ 70.1. Benzylic methylene carbon exhibited signal at δ 73.2. Peaks resonating at δ 116.4 and 138.3 were due to terminal and internal olefinic carbons respectively. Aromatic carbons showed signals at δ 127.4, 127.5, 128.3 and 136.5. The spectroscopic data confirmed the structure of compound 42.

3.1.3.2 Wacker oxidation of functionalized terminal olefins. We have developed a general and effective process for Wacker oxidation using

Pd(0) and KBrO3 as shown in fig. 32.

Figure 32

Various similar other co-oxidants were evaluated for the Wacker oxidation (Table 1). For this purpose 1-Ocetene is used as starting material for testing the different co-oxidants (Figure-33). Wacker oxidation of 1-octene with NaIO4 gave corresponding methyl ketone in trace amount only (Table 1, entry 1). Reaction using

NaOCl or K2S2O8 gave the product again in very low yields (Table 1, entries 2 and 3).

Wacker oxidation with NaBrO3 leads to 2-octanone in moderate yield (Table 1, entry 5). Decomposition of 1-octene was observed with oxone (Table 1, entry 6). This suggested that in Wacker oxidation, as compared to other oxidants KBrO3 serves as the best oxidant with Pd0/C. In conclusion we have developed a practical, general, and a green method for Wacker oxidation, which uses an inexpensive oxidant, can tolerate different functional groups, and provides product selectively in high yields. This method is of particular interest for easy recoverability and recyclability of the catalyst without any decrease in the yield of expected methyl ketones.

Figure 33

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Table-1: Screening of oxidant Yield Entry Co-Oxidant (%)

1 NaIO4 6 2 NaOCl 10

3 K2S2O8 19

4 KBrO3 84

5 NaBrO3 62 6 Oxone ----

Compounds with different functional groups were subjected to Wacker oxidation to give corresponding oxidized product as shown in Table 2. General procedure for oxidation is as follows.

To the solution of olefin in THF/water, 10% Pd/C (0.05 mmol) and KBrO3 were added and heated at reflux temperature. After completion of reaction (checked by TLC), the mixture was diluted with water and filtered through Whatman 40 filter paper. The filtrate was extracted with ethyl acetate. The combined organic layer washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by column chromatography to get the product.

Table-2: Substrate and Wacker oxidized product with yield. Entry Substrate Product Yield (%)

1 (1) (43) 84 2 86

(2) (44) 3

(4) (45) 73 4

(6) (46) 77

198

5 86 (8) (47) 6 65 (10) (48) 7 71

8 73

(15) (50) 9 78

(18) (51) 10 80

(21) 11 81

(22) 12 76

(24) 13 68 (27) (55) 14 69

(30) (56)

199

15 76 (33) (57) 16 79

(34) (58) 17 73

(36) (59) 18 84

(37) (60) 19 71

(40) (61) 20 68

(42) (62) 21 Starting recovered ----- (63)

octan-2-one (43) In the IR spectrum of 2-octanone, peaks observed at 1716 cm-1 indicates the keto group. In 1H NMR spectrum, triplet observed at δ 2.42 with coupling constant 7.6 Hz corresponded to two C-3methylene protons adjacent to ketone functionality. C-1Methyl protons adjacent to ketone functionality show singlet at 2.14. Multiplet resonated between 1.59-1.52 corresponded to two C-4methylene protons. Multiplet observed between 1.36- 1.24 attributed to six methylene protons situated at 5, 6 and 7 position.

200

Triplet resonated at 0.88 attributed to three C-8methyl protons. In the 13C NMR spectrum, signal observed at δ 209.4 attributed to carbonyl carbon. C-3 carbons resonated at 43.8, C-6 carbon at 31.5 and C-1 at 29.8. Peaks resonated at 28.8, 23.8, 22.4 and 14.0 attributed to C-5, C-4, C-7 and C-8 carbons.

1H NMR (300MHz, CDCl3) spectrum of 43

13 C NMR (75MHz, CDCl3) spectrum of 43

201

Acetophenone (44) In the IR spectrum, peak at 3029, 1360, 966, 697 cm-1 show aromatic ring while peak at 1686 cm-1 indicates the carbonyl functionality.

1 H NMR (300MHz, CDCl3) spectrum of 44

13 C NMR (75MHz, CDCl3) spectrum of 44

1H NMR spectrum show doublet of doublet at δ 7.97 with coupling constant 8 Hz and 2 Hz attributed to two ortho substituted protons. Multiplet resonated between 7.62-7.43 attributed to three protons substituted to meta and para position. Singlet at δ 2.61 corresponded to three methyl protons. In the 13C NMR spectrum, peak resonated at δ 198.0 attributed to carbonyl carbon. Peak resonating at 137.2 attributed to alpha

202 carbon from benzene ring. Para substituted carbon resonated at 133.2. Peaks resonating at 128.6 and 128.4 show ortho and meta carbons while methyl carbon atom show peak at δ 26.7.

1-(3,4-Dimethoxy-phenyl)-propan-2-one (45)

1 H NMR (300MHz, CDCl3) spectrum of 45

13 C NMR (75MHz, CDCl3) spectrum of 45

203

In the IR spectrum, peaks resonated at 2918, 1591, 1516, and 736 cm-1 indicates the presence of aromatic ring. Peak resonated at 1710 cm-1 show carbonyl group. In the 1H NMR spectrum, doublet resonated at δ 6.83 with coupling constant 7.8 Hz attributed to one aromatic proton which was othro to both, methoxy and side chain. Singlet resonated at 6.70 attributed to one meta proton respective to side chain. Doublet resonated at 6.67 with coupling constant 7.8 Hz attributed to one ortho proton respective to side chain. Singlet resonating at 3.82 attributed to six protons from methoxy group. Benzylic methylene protons resonated at 3.60 as singlet. Methyl protons alpha to carbonyl was observed to be resonated at δ 2.19 as singlet. In the 13C NMR spectrum, carbonyl carbon was resonated at δ 206.0. Meta and para carbons bearing methoxy group was observed to be resonated at δ 148.1, and 147.3. Peak resonated at 126.0 attributed to carbon bearing side chain. Carbon ortho to methoxy as well as side chain was resonated at 121.3. Peaks resonated at 112.4, and 111.1 was attributed to ortho and meta carbons with respective to side chain. Peaks resonating at 55.7, and 55.6 were attributed to methoxy carbons. Benzylic methyene carbons was resonated at 50.3 while methyl carbon neighbouring to carbonyl was observed to be resonated at 28.9.

1-Benzyloxy-propan-2-one (46)

1 H NMR (300MHz, CDCl3) spectrum of 46

In the IR spectrum, peaks at 2958, 2931, 914 and 734 cm-1 indicate the presence of benzene ring. Peak at 1735 attributed to carbonyl group. Peak at 1244 shows ether linkage. In the 1H NMR spectrum, multiplet resonating between δ 7.11-7.05 was

204 attributed to five aromatic protons. Singlet resonated at 4.40 was attributed to two benzylic methylene protons. Methylene protons neighbouring to carbonyl was resonated at 3.84 as singlet. Singlet resonated at 1.96 was corresponded to three methyl protons.

13 C NMR (75MHz, CDCl3) spectrum of 46

In the 13C NMR spectrum, carbonyl carbon was resonated at δ 205.9. Aromatic carbons were resonated at 136.8, 128.0, 127.9, 127.5, 127.4, 127.3, and 127.2. Methylene carbon alpha to carbonyl was resonated at 74.8 while benzylic methylene carbon was resonated at 72.8. Peak resonated at 26.0 was attributed to methyl carbon.

1-(2,6-Dimethylphenoxy)propan-2-one (47)

1 H NMR (300MHz, CDCl3) spectrum of 47

205

13 C NMR (75MHz, CDCl3) spectrum of 47

Benzoic acid 2-oxo-propyl ester (48)

1 H NMR (300MHz, CDCl3) spectrum of 48

In the IR spectrum, peaks resonating at 1724 and 1723 cm-1 attributed to carbonyl functionality. Peak at 1118 cm-1 indicates the ether linkage. In the 1H NMR spectrum, doublet resonated at δ 8.00 with coupling constant 7.1 and 2 Hz was attributed to two ortho substituted protons. Triplet resonated at 7.52 with coupling constant 7.4 was attributed to para substituted proton, while tiplet resonated at 7.37 with coupling

206 constant 7.7 Hz was attributed to two meta substituted protons. Singlet observed at 4.79 corresponded to methylene protons and singlet resonated at 2.14 was attributed to methyl protons

13 C NMR (75MHz, CDCl3) spectrum of 48

. In the 13C NMR spectrum, signal resonated at δ 201 was attributed to carbonyl carbon from ketone functionality while peak resonated at 165 was attributed to carbonyl carbon from ester functionality. Signals resonating at 133.0, 129.6, 129.4, and 128.1 were corresponded to aromatic carbons from benzene ring. Peak resonated at 68.4 was attributed to bridged methylene carbon while peak observed at 25.8 corresponded to methyl carbon.

3, 5-Dinitro-benzoic acid 2-oxo-propyl ester (49) IR spectrum shows signals resonated at 1734 and 1729 cm-1 indicating the presence of ester and ketone functionality. In the 1H NMR spectrum, singlet resonated at δ 9.21and 9.16 attributed to one para substituted proton and two ortho substituted protons with respective to ester functionality. Bridged methylene protons were resonated at 5.08 as singlet and methyl protons also show singlet at 2.24. In the 13C NMR spectrum, signal resonating at δ 199.2 and 164.3 were attributed to carbonyl carbons from ketone and ester functionality. Two meta substituted carbons bearing nitro group was observed to be resonated at 148.5. Peak at 129.5 corresponded to C-1 carbon from benzene ring. Signals resonated at 129.3 and 122.3 corresponds to ortho and para carbons. Signal resonating at 69.5 and 25.9 were corresponded to bridged methylene and methyl carbons.

207

1 H NMR (300MHz, CDCl3) spectrum of 49

13 C NMR (75MHz, CDCl3) spectrum of 49

2-(2-Chloro-phenyl)-4-oxo-pentanal (50) In the IR spectrum, peak at 1718 cm-1 indicates the presence of carbonyl functionality. Peaks resonating at 2922, 2850, 1718 and 1694 cm-1 corresponded to benzene or aromatic ring. 1H NMR spectrum show singlet at δ 9.60 corresponded to aldehyde functionality. Doublet of doublet resonating at 7.45 was attributed to ortho proton respective to chloro group. Multiplet resonating at 7.28 attributed to two meta substituted protons respective to chloro substituent. Doublet of doublet resonating at

208

7.11 with coupling constant 9 and 3.5 Hz corresponded to para proton with respective to chloro atom. Doublet of doublet resonating at 4.62 with coupling constant 12.9 and 4.4 Hz was attributed to one methine proton alpha to aldehyde functionality. Two doublet of doublet were observed at 3.39 and 2.71 attributed to two bridged methylene protons. Singlet at 2.23 was attributed to three methyl protons.

1 H NMR (300MHz, CDCl3) spectrum of 50

13 C NMR (75MHz, CDCl3) spectrum of 50

In the 13C NMR spectrum, peak observed at δ 205.1 attributed to carbonyl carbon from ketone, while peak resonated at 198.1 corresponded to carbon from aldehyde functionality. Aromatic carbons were resonated at 134.2, 133.5, 130.2, 130.1, 129.1,

209 and 127.3. Methine carbon alpha to aldehyde was observed to resonate at 50.6. Bridged methylene carbon was observed to be resonated at 42.5 and methyl carbon at 29.9.

2-(2-Nitro-phenyl)-4-oxo-pentanal (51)

1 H NMR (300MHz, CDCl3) spectrum of 51

In the IR spectrum, peak at 1718 and 1696 cm-1 indicates the presence of carbonyl functionality from ketone and aldehyde. Peaks resonating at 2839, 1608, 1525 and 746 cm-1 corresponded to benzene ring.

13 C NMR (75MHz, CDCl3) spectrum of 51

210

1H NMR spectrum show singlet at δ 9.70 corresponded to proton from aldehyde functionality. Doublet resonating at 8.00 with coupling constant 8 Hz was attributed to ortho proton respective to nitro group. Triplet resonating at 7.63 attributed to one meta substituted protons respective to nitro substituent. Triplet resonating at 7.56 with coupling constant 7.9 corresponded to meta proton with respective to nitro atom. Doublet resonating at 7.39 with coupling constant 8 Hz attributed to one para substituted proton with respective to ntiro substituent. Doublet of doublet resonating at 4.66 with coupling constant 7.6 and 5.3 Hz was attributed to one methine proton alpha to aldehyde functionality. Two doublet of doublet were observed at 3.47 and 2.83 attributed to two bridged methylene protons. Singlet at 2.19 was attributed to three methyl protons. In the 13C NMR spectrum, peak observed at δ 204.7 attributed to carbonyl carbon from ketone, while peak resonated at 197.4 corresponded to carbon from aldehyde functionality. Carbon atom bearing nitro group was resonated at 149.0. Aromatic carbons were resonated at 133.5, 131.4, 130.8, 128.7, and 125.2. Methine carbon alpha to aldehyde was observed to resonate at 48.2. Bridged methylene carbon was observed to be resonated at 43.4 and methyl carbon at 29.6.

2-(3,4-Dimethoxy-phenyl)-4-oxo-pentanal (52) In the IR spectrum, peak resonating at 1721 and 1698 cm-1 corresponded to carbonyl functionality from aldehyde and ketone.

1 H NMR (300MHz, CDCl3) spectrum of 52

211

13 C NMR (75MHz, CDCl3) spectrum of 52

In the 1H NMR spectrum, singlet resonating at δ 9.64 attributed to proton from aldehyde. Aromatic protons from the benzene ring were resonated between 7.00-6.65. Benzylic methine proton was resonated at 4.25 as doublet of doublet with coupling constant 18.6 and 8.8 Hz. Two singlet’s were observed at 3.91and 3.86 corresponded to three protons each from methoxy group. Two protons from bridged methylene group was observed to be resonated at 3.31and 2.72 as doublet of doublet. Singlet resonating at 2.20 corresponded to three methyl protons. In the 13C NMR spectrum, peaks resonated at δ 205.8 and 198.5 was corresponded to ketone and aldehyde carbons. Carbons bearing methoxy group were resonated at 149.3 and 148.5. Peaks resonating at 127.2, 121.1, 111.7 and 111.6 corresponded to aromatic protons. Two carbons from methoxy group were resonated at 55.9. Methine carbon was resonated at 52.5. Bridged methylene carbon was resonated at 43.8 while methyl carbon at 33.2.

5-(Benzyloxy)-4-(3,4-dimethoxyphenyl)pentan-2-one (53) In the IR spectrum, peak at 1710 cm-1 corresponded to ketone functionality. Peak at 1236 indicates the ether linkage. 1H NMR spectrum shown multiplet resonating between δ 7.34 -7.23 attributed to five protons from benzyl ring. Multiplet resonating between 6.81-6.74 attributed to three aromatic protons from parent benzene ring. Benzyl methylene protons were resonated at 4.48 as singlet. Six methoxy protons were resonated as singlet at 3.84. Multiplet resonating between 3.64- 3.44 attributed to one methine proton and two methylene protons from carbon carrying benzyl group. Two doublet of doublet were observed at 2.96 and 2.71 attributed to two bridged methylene

212 protons neighboring to ketone functionality. Singlet resonating at 2.06 was attributed to three methyl protons.

1 H NMR (300MHz, CDCl3) spectrum of 53

13 C NMR (75MHz, CDCl3) spectrum of 53

In the 13C NMR spectrum, peak resonating at δ 207.6 attributed to carbonyl carbon. Signals resonating at 148.7 and 147.6 corresponded to two benzene carbons carrying methoxy groups. Peaks resonated at 138.1 and 134.4 were attributed to C-1 and C-1ʹ from benzene rings. Peaks resonated at 128.2 and 127.4 corresponded to carbons from benzyl group while peaks resonating at 119.4, 111.1 and 111.0 corresponded to carbons

213 from benzene ring. Two methylene carbons attached to oxygen atom were resonated at 74.1 and 72.9. Methoxy carbons were resonated at 55.7 while bridged methylene carbon neighboring to ketone was observed to resonate at 46.9. Peak resonated at 40.8 was attributed to benzylic methine carbon. Methyl carbon was resonated at 30.4.

3-(Benzyloxy)-3-(3,4-dimethoxyphenyl)propanal (54)

1 H NMR (300MHz, CDCl3) spectrum of 54

13 C NMR (75MHz, CDCl3) spectrum of 54

214

In the IR spectrum, signal resonating at 1725 cm-1 indicates the aldehyde functionality. In the 1H NMR spectrum, doublet at 9.77 with coupling constant 1.7 Hz attributed to proton from aldehyde functionality. Multiplet resonating between 7.27-7.36 attributed to five aromatic protons from benzyl group. Aromatic protons resonate as multiplet between 6.92-6.86 attributed to three protons. Methine proton at benzylic position was observed to resonated at 4.85 showing doublet of doublet with coupling constant 8.8 and 4.1 Hz. Benzyl methylene protons show quartet with coupling constant 11.7 attributed to two protons. Singlet resonated at 3.89 attributed to six methoxy protons. Multiplets resonating at 2.98 and 2.69 attributed to two methylene protons alpha to aldehyde functionality. In the 13C NMR spectrum, signal resonating at δ 200.5 attributed to carbon from aldehyde group. Peaks resonating at 152.8 and 149.2 attributed to aromatic carbons bearing methoxy groups. Peaks resonating at 132.7, 119.1, 110.9 and 109.1 attributed to aromatic carbons from benzene ring bearing methoxy groups. Peaks resonated at 137.7, 128.3, 127.8 and 127.6 attributed to carbons from benzyl group. Peak observed at 75.8 attributed to benzylic methine carbon. Signal resonated at 70.2 was corresponded to benzylic methylene carbon. Carbons from methoxy groups were resonated at 55.7 while methylene carbon alpha to aldehyde was resonated at 51.5.

3-Oxo-1-phenylbutyl benzoate (55)

1 H NMR (300MHz, CDCl3) spectrum of 55

215

In the IR spectrum, signal at 1726 cm-1 show ketone functionality. In the 1H NMR spectrum, multiplet resonating between δ 8.12- 8.02 attributed to ortho substituted proton from benzoyl group. Multiplet resonating between 7.58- 7.30 was attributed to three protons from benzoyl group and five protons from aromatic ring. Methine proton at benzylic position was resonated at 6.44 as doublet of doublet with coupling constant 8 Hz and 4 Hz. Two multiplets resonating at 3.28 and 2.97 attributed to one proton each from bridged methylene carbon while three methyl protons were resonated at 2.18 show singlet.

13 C NMR (75MHz, CDCl3) spectrum of 55

In the 13C NMR spectrum, peaks resonating at δ 204.7 and 201.0 were due to carbonyl carbon from ketone and ester functionality. Peak resonated at 72.4 was due to benzylic methine carbon. Methyl carbon and methylene carbon alpha to ketone were resonated at 50.1 and 30.5 respectively.

(R)-4-(benzyloxy)-4-((3aR,5R,6R,6aR)-6-(benzyloxy)-2,2- dimethyltetrahydrofuro[3,2-d] [1,3]dioxol-5-yl)butan-2-one (56) In the IR spectrum, peak resonated at 1716 cm-1 indicates the presence of ketone functionality. Peaks at 1093 and 1026 cm-1 indicates the presence of ether linkage. Peaks at 2926, 1454, 1375, 1217 and 742 resonated for aromatic region. In the 1H NMR spectrum, multiplet resonating between δ 7.38-7.21was attributed to ten protons from

216 two benzyl groups. Doublet at 5.67 with coupling constant 3.7 was attributed to 2H proton. Multiplet resonating between 4.78-4.51 was attributed to ten aromatic protons from benzyl ring. Multiplet resonating between 4.33-4.30 and doublet at 4.14 indicates 3H and 5H protons. Two doublet of doublet was observed at 3.96 and 2.77 were corresponded to 4H and 6H protons. Two methylene protons adjacent to ketone were resonated at 2.55 as doublet of doublet while methyl protons were resonated as singlet at 2.05. Six methyl protons from dioxole ring were resonated at 1.57 and 1.35 as two singlet’s, three for each.

1 H NMR (300MHz, CDCl3) spectrum of 56

13 C NMR (75MHz, CDCl3) spectrum of 56

217

In the 13C NMR spectrum, peak at δ 206.4 indicates the presence of carbonyl carbon. Signals resonating at 138.6, 137.3, 128.3 and 128.1were attributed to aromatic carbons from two benzyl ring. Carbon carrying dimethyl from dioxole ring was resonated at 112.9 and C-1 carbon at 80.6. Signals appeared at 77.4, 77.1 and 74.1were due to C2, C3 and C4 carbon. Two methylene carbons from benzyl were resonated at 73. Peaks resonated at 71.9 and 44.8 were due to C5 and C6 carbons. Methyl carbon neighboring to ketone was resonated at 30.6. Two methyl carbons from dioxole ring were resonated at 26.8 and 26.5.

(3aR,5R,6S,6aR)-2,2-Dimethyl-5-(2-oxoethyl)tetrahydrofuro[3,2-d][1,3]dioxol-6-yl- 4-methyl benzenesulfonate (57) We subjected olefinic compound 31 wacker oxidation process under similar conditions. In this case we gate aldehyde as oxidized product instand of methyl ketone (Figure 34). This may be due to α-substitution.38

Figure 34

1 H NMR (300MHz, CDCl3) spectrum of 57

218

In the IR spectrum, a peak at 1727 cm-1 corresponded to aldehyde functionality. Signals resonating at 1496, 1372 and 1244 cm-1 corresponded to benzene ring while peaks at 1150 and 1077 indicate ether linkage.

13 C NMR (75MHz, CDCl3) spectrum of 57

In the 1H NMR spectrum, peak resonating at δ 9.56 as singlet was attributed to aldehyde proton. Doublet observed at 7.78 and 7.38 with coupling constant 8.2 Hz attributed to ortho and meta substituted protons from tosyl benzene ring. Doublet resonating at 5.89 and 4.85 were due to H4 and H1 protons. Multiplet resonating between 4.67-4.62 was attributed to H3 and H5 protons. One proton form methylene adjacent to aldehyde functionality show doublet of doublet at 2.82 with coupling constant 18.2 Hz and 7 Hz while second proton show doublet of doublet at 2.67 with coupling constant 18.2 and 5.7 Hz. Methyl protons from tosyl ring was resonated at 2.47 as singlet. Two singlet’s resonating at 1.49 and 1.29 were corresponded to methyl protons from dioxole ring. In the 13C NMR spectrum, signal resonating at δ 198.1 corresponded to carbonyl carbon of aldehyde functionality. Signals resonating at 145.7, 132.5, 130.1 and 127.9 corresponded to aromatic carbons from tosyl ring. Signal observed at 112.4 was due to carbon bearing dimethyl from dioxole ring. Signals resonating at 104.2, 83.3, 82.5 and

219

73.6 corresponded to C1, C2, C3 and C4 carbons. Methylene carbon was observed to be resonated at 42. Signal at 21.7 was attributed to methyl from tosyl ring. Peaks resonating at 26.5 and 26.2 were attributed to two methyl carbons from dioxole ring.

(2R,5S)-5-Isopropyl-2-methyl-2-(2-oxopropyl)cyclohexanone (58)

1 H NMR (300MHz, CDCl3) spectrum of 58

13 C NMR (75MHz, CDCl3) spectrum of 58

220

In the IR spectrum strong absorption band at 1708 cm-1 corresponded to two overlapping ketone groups. In 1H NMR spectrum, the diastereotopic proton from methylene group adjacent to the methyl ketone appeared at 2.68 as a doublet with coupling constant 16.2 Hz. Doublet at 2.37 corresponded to methylene protons alpha to the ring ketone with coupling constant 6.6 Hz. The methyl ketone showed a singlet at 2.13. The methylene protons alpha to ring ketone was resonated in the range δ 1.98-2.05 as a broad doublet with coupling constant 15.1 Hz. A multiplet between 1.54-1.74 integrating for five protons corresponded to two ring methylene groups and isopropyl methine proton. A singlet was observed at 1.09 was due to the quaternary methyl group alpha to carbonyl in the ring. A doublet at 0.90 was due to the gem. dimethyl groups with coupling constant of 6.0 Hz. In the 13C NMR spectrum, two carbonyl groups appeared at 206.6 and 214 corresponded to methyl ketone and due to the cyclic ketone. Three carbons alpha to the two carbonyl groups appeared at 41.7, 45.6 and 46.7 while quaternary carbon appeared at 50.7. The peaks at 24.1, 31.4, 31.8 and 37.4 were due to the two methylene carbons and two methine groups in the ring. Signals at 19.7 and 19.8 corresponded to two geminal dimethyl groups while the quaternary methyl group appeared at 22.9.

1-((1R,2S,4S)-4-Isopropyl-2-methoxy-1-methylcyclohexyl)propan-2-one (59)

1 H NMR (300MHz, CDCl3) spectrum of 59

221

13 C NMR (75MHz, CDCl3) spectrum of 59

In the IR spectrum, peak at 1723 cm-1 show ketone and peak at 1087 cm-1 indicated the ether linkage. In the 1H NMR spectrum, singlet resonating at δ 3.27 for three protons attributed to methoxy protons. Doublet of doublet resonating at 2.73 attributed to methine proton alpha to methoxy. Quartet resonating at 2.45 attributed to two methylene protons neighbouring to ketone while methyl protons was resonated at 2.14 as singlet. Multiplet resonating between 1.99-1.83 attributed to methine from isopropyl ring methylene from cycylohexyl ring. Singlet resonated at 1.10 was corresponded to methyl protons from cyclohexene ring. Methyl protons from isopropyl were observed to be resonated at 0.89 and 0.87 as doublet. In the 13C NMR spectrum, peak resonating at δ 210.1 was attributed to carbonyl carbon. Methine carbon bearing methoxy group was resonated at 88.3 while carbon from methoxy was resonated at 57.6. Methylene carbon adjacent to ketone was observed at 43.0. Methine carbons from cyclohexene ring carrying isopropyl and methyl was resonated at 38.8 and 35.2 respectively. Methine from isopropyl and methyl adjacent to ketone was resonated at 32.7 and 32.6. Methyl from cyclohexene and isopropyl were resonated 24.6, 19.9 and 19.8. Methylene from cyclohexyl ring were resonated at 33.0, 29.2 and 25.8.

(2S,3R,6S)-6-Isopropyl-3-methyl-2-(2-oxopropyl)cyclohexanone (60) In the IR spectrum two strong absorption bands at 1716 cm-1 and 1699cm-1 corresponded to two ketone groups.1HNMR spectrum showed a doublet at 2.96 was due to one of the diastereotopic methylene proton adjacent to ketone with coupling constant of 16.7Hz. Another proton from methylene adjacent to ketone and two methine protons

222 from cyclohexyl ring shows multiplet at 2.16. Nine methylene protons were resonated between 2.45-1.67 while doublet at 0.88 and 0.72 due to the gem.dimethyl groups with identical coupling constant of 6.8 Hz

1 H NMR (300MHz, CDCl3) spectrum of 60

13 C NMR (75MHz, CDCl3) spectrum of 60

In 13C NMR spectrum, peaks observed at 207.7 and 213.2 attributed to cyclo ketone and methyl ketone. Peaks at 53.0 and 47.6 attributed to carbons adjacent to cyclo ketone bearing isopropyl and side chain respectively. Two carbons adjacent to the methyl ketones appeared at 42.8, and 33.3. The peaks at 29.6, 30.2, 31.4, and 31.6 were

223 corresponded to four aliphatic carbons of the ring. Signals observed at 17, 17.2, and 22.4 were due to the three methyl groups.

(R)-4-(Benzyloxy)-4-(1,4-dioxaspiro[4.5]decan-2-yl)butan-2-one (61)

1 H NMR (300MHz, CDCl3) spectrum of 61

13 C NMR (75MHz, CDCl3) spectrum of 61

In the IR spectral data, signal appeared at 1722 cm-1 indicates the presence of ketone functionality while peak at 1097 indicates ether linkage. In the 1H NMR spectrum, multiplet resonating between δ 7.37-7.30 was attributed to five aromatic protons from benzyl ring. Singlet resonated at 4.60 corresponded to two benzylic methylene protons. Multiplet resonating between 4.06-4.01 and 3.83-3.80 attributed to two methylene

224 protons and one methine proton from dioxolane ring. Multiplet resonating between 2.75-2.68 was attributed to one methine proton alpha to benzyl and two methylene protons adjacent to ketone. Singlet at 2.18 was due to protons from methyl neighboring to ketone. Multiplet resonating between 1.59-1.26 was attributed to methylene protons from cyclohexyl ring. 13C NMR spectral data shows signal at δ 207.0 attributed to carbonyl karbon. Peaks resonating at 128.4, 127.9 and 127.8 were attributed to aromatic carbons from benzyl ring. Methine carbon of the dioxolane ring was resonated at 77.2 while methylene carbon was resonated at 66.5. Benzylic methylene was resonated 76.5 while methine carbon bearing benzyl was resonated at 73.1. Signals resonating at 46.2 and 25.2 corresponded to methylene and methyl carbons neighboring to ketone. Signals resonating at 36.2, 34.7, 31.2, 24.0 and 23.8 were due to methylene carbons of cyclohexyl ring.

(R)-5-(Benzyloxy)-4-((S)-1,4-dioxaspiro[4.5]decan-2-yl)pentan-2-one (62) In the IR spectral data, signal appeared at 1712 cm-1 indicates the presence of ketone functionality while peak at 1099 indicates ether linkage.

1 H NMR (300MHz, CDCl3) spectrum of 62

In the 1H NMR spectrum, multiplet resonating between δ 7.36-7.27 was attributed to five aromatic protons from benzyl ring. Singlet resonated at 4.44 corresponded to two benzylic methylene protons. Multiplet resonating between 4.09-3.99 and 3.66-3.60 attributed to two methylene protons and one methine proton from dioxolane ring. Multiplet resonating between 3.42-3.35 was attributed to two methylene protons bearing

225 benzyl group. A multiplet resonating between 2.44-2.41 was attributed to one methine proton beta to benzyl and two methylene protons adjacent to ketone were resonated at 2.71 and 2.45 as doublet of doublet. Singlet at 2.16 was due to protons from methyl neighboring to ketone. Multiplet resonating between 1.61-1.24 was attributed to methylene protons from cyclohexyl ring.

13 C NMR (75MHz, CDCl3) spectrum of 62

13C NMR spectral data shows signal at δ 208.0 attributed to carbonyl carbon. Peaks resonating at 128.3, 127.6 and 127.5 were attributed to aromatic carbons from benzyl ring. Methine carbon of the dioxolane ring was resonated at 76.3 while methylene carbon was resonated at 68.0. Benzylic methylene was resonated 73.1 and methylene carbon bearing benzyl was resonated at 70.5. Signals resonating at 42.2 and 30.5 corresponded to methylene and methyl carbons neighbouring to ketone. Signal resonated at 36.1 was attributed to methine carbon neighbouring to cyclohexyl ring. Signals resonating at 38.7, 35.0, 32.7, 25.1 and 23.9 were due to methylene carbons of cyclohexyl ring.

226

3.1.4 Experimental section Chemicals were either purchased or purified by standard techniques without special instructions. All solvents were distilled before use. Silica gel (100–200 mesh) was used for column chromatography. IR spectra were recorded on a Shimadzu FT-IR- 8400 series instrument. 1H NMR spectra were recorded on VARIAN Mercury 300 MHz 13 instrument by using CDCl3 as internal standard. C NMR spectra were recorded on Varian Mercury 75 MHz instrument. Optical rotations were measured on a JASCO-181 digital polarimeter. The elemental analysis was obtained on a HOSLI semiautomatic C, H analyzer. 0 Typical experimental procedure for Wacker oxidation with 10% Pd /C-KBrO3 To the solution of olefin (1 mmol), in THF/water (4:1, 15 ml), 10% Pd/C (0.05 mmol) and KBrO3 (3 mmol) were added. This mixture was heated at reflux temperature. After completion of reaction (checked by TLC), the mixture was diluted with water and filtered through Whatman 40 filter paper. The filtrate was extracted with ethyl acetate. The combined organic layer washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by column chromatography to get the product. Octan-2-one (43) IR (Neat, cm-1): 2928, 1716, 1458, 1363, 1165, and 1037. 1 H NMR (300 MHz, CDCl3): δ 2.42 (t, 2H, J = 7.6 Hz), 2.14 (s, 3H), 1.59-1.52 (m, 2H), 1.36- 1.24 (m, 6H), 0.88 (t, 3H, J = 13 6.5 Hz); C NMR (75 MHz, CDCl3): δ 209.4, 43.8, 31.5,

29.8, 28.8, 23.8, 22.4, 14.0; Anal. Calcd. for C8H16O: C, 74.94; H, 12.58. Found: C, 74.81; H, 12.63.

Acetophenone (44) IR (Neat, cm-1): 3029, 1686, 1360, 1267, 966, 697. 1 H NMR (300 MHz, CDCl3): δ 7.97 (dd, 2H, J = 8 & 2 Hz), 7.62- 13 7.43 (m, 3H), 2.61 (s, 3H); C NMR (75 MHz, CDCl3): δ 198.0,

137.2, 133.2, 128.6, 128.4, 26.7; Anal. Calcd. for C8H8O: C, 79.97; H, 6.71. Found: C, 80.09; H, 6.77.

1-(3,4-Dimethoxy-phenyl)-propan-2-one (45) IR (Neat, cm-1): 2918, 1710, 1591, 1516, 1263, 1236, 736.

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1 H NMR (300 MHz, CDCl3): δ 6.83 (d, 1H, J = 7.8 Hz), 6.70 (s, 1H), 6.67 (d, 2H, J = 13 7.8 Hz), 3.82 (s, 6H), 3.60 (s, 2H), 2.19 (s, 3H); C NMR (75 MHz, CDCl3): δ 206.0, 148.1, 147.3, 126.0, 121.3, 112.4, 111.1, 55.7, 55.6, 50.3, 28.9. Anal. Calcd. for

C11H14O3: C, 68.02; H, 7.27. Found: C, 67.92; H, 7.38.

1-Benzyloxy-propan-2-one (46) IR (Neat, cm-1): 2958, 2931, 1735, 1369, 1244, 914, 734. 1 H NMR (300 MHz, CDCl3): δ 7.11-7.05 (m, 5H), 4.40 (s, 13 2H), 3.84 (s, 2H), 1.96 (s, 3H); C NMR (75 MHz, CDCl3): δ 205.9, 136.8, 128.0,

127.9, 127.5, 127.4, 127.3, 127.2, 74.8, 72.8, 26.0; Anal. Calcd. for C10H12O2: C, 73.15; H, 7.37. Found: C, 72.96; H, 7.43.

1-(2,6-Dimethylphenoxy)propan-2-one (47) 1 H NMR (300 MHz, CDCl3): δ 7.02- 6.91 (m, 3H), 4.34 (s, 13 2H), 2.34 (s, 3H), 2.27 (s, 6H); C NMR (75 MHz, CDCl3): δ 205.3, 154.8, 130.4, 128.9, 124.3, 76.4, 26.5, 16.1;Anal. Calcd. for C11H14O2: C, 74.13; H, 7.92. Found: C, 74.28; H, 8.01.

Benzoic acid 2-oxo-propyl ester (48) IR (Neat, cm-1): 3066, 2931, 1724, 1723, 1278, 1118, 910, 713. 1 H NMR (300 MHz, CDCl3): δ 8.00 (d, J = 7.1, 2H), 7.52 (t, 1H, J = 7.4Hz), 7.37 (t, 2H, J = 7.7), 4.79 (s, 2H), 2.14 (s, 13 3H); C NMR (75 MHz, CDCl3): δ 201, 165, 133.0, 129.6, 129.4, 128.1, 68.4, 25.8;

Anal. Calcd. for C10H10O3: C, 67.41; H, 5.66. Found: C, 67.26; H, 5.70.

3, 5-Dinitro-benzoic acid 2-oxo-propyl ester (49) IR (Neat, cm-1): 2929, 2330, 1734, 1729, 1546, 1346, 1 1269, 740. H NMR (300 MHz, CDCl3): δ 9.21 (s, 1H), 9.16 (s, 2H), 5.08 (s, 2H), 2.24 (s, 3H); 13C NMR (75

MHz, CDCl3): δ 99.2, 164.3, 148.5, 129.5, 129.3, 122.3,

69.5, 25.9; Anal. Calcd. for C10H8N2O7: C, 44.79; H, 3.01; N, 10.45. Found: C, 44.87; H, 2.91; N, 10.63.

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2-(2-Chloro-phenyl)-4-oxo-pentanal (50) IR (Neat, cm-1): 2922, 2850, 2254, 1718, 1694, 1037. 1 H NMR (300 MHz, CDCl3): δ 9.60 (s, 1H), 7.45 (dd, 1H, J = 9.0 Hz & 3.5 Hz), 7.28 (m, 2H), 7.11 (dd, 1H, J = 9.0 Hz & 3.5 Hz), 4.62 (dd, 1H, J = 12.9 Hz & 4.4 Hz), 3.39 (dd, 1H, J = 16.6 Hz & 8.8 Hz), 2.71 (dd, 1H, J = 12.3 Hz & 4.4 Hz), 2.23 (s, 3H); 13C NMR (75

MHz, CDCl3): δ 205.1, 198.1, 134.2, 133.5, 130.2, 130.1, 129.1, 127.3, 50.6, 42.5, 29.9;

Anal. Calcd. for C11H11ClO2: C, 62.72; H, 5.26. Found: C, 62.89; H, 5.16.

2-(2-Nitro-phenyl)-4-oxo-pentanal (51) IR (Neat, cm-1): 2839, 1718, 1696, 1608, 1525, 1352, 1238, 1168, 746. 1 H NMR (300 MHz, CDCl3): δ 9.70 (s, 1H), 8.00 (d, 1H, J = 8.0 Hz), 7.63 (t, 1H, J = 7.4 Hz), 7.56 (t, 1H, J = 7.9 Hz) 7.39 (d, 1H, J = 8.0 Hz), 4.66 (dd, 1H, J = 7.6 & 5.3 Hz) 3.47 (dd, 1H, J = 18.1 & 7.6 Hz), 2.83 (dd, 1H, J=18.1 & 5.3 Hz), 2.19 (s, 3H); 13C NMR (75 MHz,

CDCl3): δ 204.7, 197.4, 149.0, 133.5, 131.4, 130.8, 128.7, 125.2,

48.2, 43.4, 29.6; Anal. Calcd. for C11H11NO4: C, 59.73; H, 5.01; N, 6.33. Found: C, 59.65; H, 4.93; N, 6.51.

2-(3,4-Dimethoxy-phenyl)-4-oxo-pentanal (52) IR (Neat, cm-1): 2685, 1721, 1698. 1 H NMR (300 MHz, CDCl3): δ 9.64 (s, 1H), 6.90 (d, J = 7.6 Hz, 1H), 6.73 (d, J = 7.6 Hz, 1H), 6.67 (s, 1H), 4.15 (dd, 1H, J = 18.6 Hz & 8.8 Hz), 3.91 (s, 3H), 3.86 (s, 3H), 3.31 (dd, 1H, J = 12.9 Hz & 4.4 Hz), 2.72 (dd, 1H, J = 17.3 Hz & 4.4 Hz), 2.20 (s, 3H); 13C

NMR (75 MHz, CDCl3): δ 205.8, 198.5, 149.3, 148.5, 127.2, 121.1, 111.7, 111.6, 55.9,

52.5, 33.2, 43.8; Anal. Calcd. for C13H16O4: C, 66.09; H, 6.83. Found: C, 65.95; H, 6.91.

5-(Benzyloxy)-4-(3,4-dimethoxyphenyl)pentan-2-one (53) IR (Neat, cm-1): 2918, 1710, 1516, 1236, 736. 1 H NMR (300 MHz, CDCl3): δ 7.34 -7.23 (m, 5H), 6.81- 6.74 (m, 3H), 4.48 (s, 2H), 3.84 (s, 6H), 3.64- 3.44 (m, 3H), 2.96 (dd, J = 16.4 & 5.8 Hz), 2.71 (dd, J = 16.4 & 7.6 Hz), 2.06 (s, 3H);

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13 C NMR (75 MHz, CDCl3): δ 207.6, 148.7, 147.6, 138.1, 134.4, 128.2, 127.4, 119.4,

111.1, 111.0, 74.1, 72.9, 55.7, 46.9, 40.8, 30.4; Anal. Calcd. for C20H24O4: C, 73.15; H, 7.37. Found: C, 73.34; H, 7.26.

3-(Benzyloxy)-3-(3,4-dimethoxyphenyl)propanal (54) IR (Neat, cm-1): 2918, 1725, 1577, 1238, and 1071. 1 H NMR (300 MHz, CDCl3): δ 9.77 (d, 1H, J = 1.7 Hz), 7.27-7.36 (m, 5H), 6.92-6.86 (m, 3H), 4.85 (dd, 1H, J = 8.8 & 4.1 Hz), 4.39 (q, 2H, J = 11.7 Hz), 3.89 (s, 6H), 2.98 (ddd, 1H, J = 16.4, 8.8, & 2.3 Hz), 2.69 (ddd, 1H, J = 16.4, 4.1 & 1.7 Hz); 13C

NMR (75 MHz, CDCl3): δ 200.5, 152.8, 149.2, 137.7, 132.7, 128.3, 127.8, 127.6,

119.1, 110.9, 109.1, 75.8, 70.2, 55.7, 51.5; Anal. Calcd. for C18H20O4: C, 71.98; H, 6.71. Found: C, 71.88; H, 6.83.

3-Oxo-1-phenylbutyl benzoate (55) IR (Neat, cm-1): 3078, 2986, 1726, 1723, 1286, 1117. 1 H NMR (300 MHz, CDCl3): δ 8.12- 8.02 (m, 2H), 7.58- 7.30 (m, 8H), 6.44 (dd, 1H, J = 8.0 & 4.0 Hz), 3.28 (dd, 1H, J = 17.0 & 8.1 Hz), 2.97 (dd, 1H, J = 17.0 & 4.0 Hz), 2.18 (s, 3H); 13C NMR (75 MHz,

CDCl3): δ 204.7, 201.0, 165.5, 139.7, 133.2, 129.7, 128.7, 128.5, 128.4, 128.3, 126.5,

72.4, 50.1, 30.5; Anal. Calcd. for C17H16O3: C, 76.10; H, 6.01. Found: C, 76.18; H, 6.09.

(R)-4-(benzyloxy)-4-((3aR,5R,6R,6aR)-6-(benzyloxy)-2,2- dimethyltetrahydrofuro[3,2-d] [1,3]dioxol-5-yl)butan-2-one (56) IR (Neat, cm-1): 2926, 1716, 1454, 1375, 1217, 1093, 1026, 742. 1 H NMR (300 MHz, CDCl3): δ 7.38-7.21 (m, 10H), 5,67 (d, 1H, J = 3.7 Hz), 4.78-4.51 (m, 5H), 4.33-4.30 (m, 1H), 4.14 (d, 1H, J = 8.5 Hz), 3.96 (dd, 1H, J = 8.6 & 4.8 Hz), 2.77 (dd, 1H, J = 17.1 & 8.5 Hz), 2.55 (dd, 1H, J = 17.1 & 4.9 Hz), 2.05 (s, 3H), 1.57 (s, 13 3H), 1.35 (s, 3H); C NMR (75 MHz, CDCl3): δ 206.4, 138.6, 137.3, 128.3, 128.1, 128.0, 127.8, 127.5, 127.3, 112.9, 103.8, 80.6, 77.4, 77.1, 74.1, 73.7, 71.9, 44.8, 30.6,

26.8, 26.5; = +93.91 (c 2.43, CHCl3); Anal. Calcd. for C25H30O6: C, 70.40; H, 7.09. Found: C, 70.49; H, 7.21.

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(3aR,5R,6S,6aR)-2,2-Dimethyl-5-(2-oxoethyl)tetrahydrofuro[3,2-d][1,3]dioxol-6-yl- 4-methyl benzenesulfonate (57) IR (Neat, cm-1): 2927, 1727, 1496, 1372, 1244, 1150, 1077. 1 H NMR (300 MHz, CDCl3): δ 9.56 (s, 1H), 7.78 (d, 1H, J = 8.2 Hz), 7.38 (d, 1H, J = 8.2 Hz), 5.89 (d, 1H, J = 3.5 Hz), 4.85 (d, 1H, J = 2.9 Hz), 4.67-4.62 (m, 2H), 2.82 (dd, 1H, J = 18.2 & 7.0 Hz), 2.67 (dd, 1H, J = 18.2 & 5.8 Hz), 2.47 (s, 3H), 13 1.49 (s, 3H), 1.29 (s, 3H); C NMR (75 MHz, CDCl3): δ 198.1, 145.7, 132.5, 130.1, 127.9, 112.4, 104.2, 83.3, 82.5, 73.6, 42.0, 26.5, 26.2, 21.7; = -24.95 (c 1.69,

CHCl3); Anal. Calcd. for C16H20O7S: C, 53.92; H, 5.66. Found. C, 54.07; H, 5.58.

(2R,5S)-5-Isopropyl-2-methyl-2-(2-oxopropyl)cyclohexanone (58) IR (Neat, cm-1): 1708, 1458, 1095, 914. 1 H NMR (300 MHz, CDCl3): δ 2.82 (d, J = 16.2 Hz, 1H), 2.68 (d, J = 16.5 Hz, 1H), 2.37 (d, J = 6.6 Hz, 2H), 2.13 (s, 3H), 2.01 (d, J = 15.1Hz, 2H), 1.74-1.45 (m, 5H), 1.09 (s, 13 3H), 0.90 (d, J = 6.0 Hz, 6H); C NMR (75 MHz, CDCl3): δ 214.0, 206.9, 50.8, 46.9,

45.5, 41.9, 37.4, 31.9, 31.5, 29.7, 24.2, 23.1, 19.7, 19.8; Anal. Calcd. for C13H22O2: C, 74.24; H, 10.54. Found. C, 74.36; H, 10.49.

1-((1R,2S,4S)-4-Isopropyl-2-methoxy-1-methylcyclohexyl)propan-2-one (59) IR (Neat, cm-1): 1723, 1458, 1087, 913. 1 H NMR (300 MHz, CDCl3): δ 3.27 (s, 3H), 2.73 (dd, 1H, J = 11.0 & 4.4 Hz), 2.45 (q, 2H, J = 14.3 Hz), 2.14 (s, 3H), 1.99-1.83 (m, 2H), 1.47-1.43 (m, 2H), 1.10 (s, 3H), 1.06- 0.95 (m, 4H), 0.89 (d, 3H, J = 1.6 Hz), 0.87 (d, 3H, J = 1.7 Hz); 13C NMR (75 MHz,

CDCl3): δ 210.1, 88.3, 57.6, 43.0, 38.8, 35.2, 33.0, 32.7, 32.6, 29.2, 25.8, 24.6, 19.9,

19.8; = +27.14 (c 1.69, CHCl3); Anal. Calcd. for C14H26O2: C, 74.29; H, 11.58. Found: C, 74.17; H, 11.53.

(2S,3R,6S)-6-Isopropyl-3-methyl-2-(2-oxopropyl)cyclohexanone (60) IR (Neat, cm-1): 1716, 1699, 1460, 1361, 910. 1 H NMR (300 MHz, CDCl3): δ 2.96 (d, J = 16.7 Hz, 1H), 2.16 (s, 3H), 2.45-1.62 (m, 9H), 2.16 (s, 3H), 0.99 (d, J = 6.0 Hz,

231

13 3H), 0.88 (d, J = 6.8 Hz, 3H), 0.72 (d, J = 6.8 Hz, 3H); C NMR (75 MHz, CDCl3): δ 213.1, 207.5, 53.0, 47.6, 42.7, 33.1, 31.4, 31.2, 30.0, 29.5, 28.4, 22.2, 17.0, 16.9; Anal.

Calcd. for C13H22O2: C, 74.24; H, 10.54. Found: C, 74.06; H, 10.59.

(R)-4-(Benzyloxy)-4-(1,4-dioxaspiro[4.5]decan-2-yl)butan-2-one (61) IR (Neat, cm-1): 2928, 2860, 1722, 1596, 1097, 736. 1 H NMR (300 MHz, CDCl3): δ 7.37-7.30 (m, 5H), 4.60 (s, 2H), 4.06-4.01 (m, 2H), 3.83-3.80 (m, 1H), 2.75-2.68 (m, 2H), 2.18 (s, 3H), 1.59-1.26 (m, 10H); 13C NMR (75 MHz,

CDCl3): δ 207.0, 138.2, 128.4, 127.9, 127.8, 110.0, 77.2, 76.5, 73.1, 66.5, 46.2, 36.2, 34.7, 31.2, 25.2, 24.0, 23.8.

(R)-5-(Benzyloxy)-4-((S)-1,4-dioxaspiro[4.5]decan-2-yl)pentan-2-one (62) IR (Neat, cm-1): 2933, 2858, 1712, 1591, 1099, 740. 1 H NMR (300 MHz, CDCl3): δ 7.36-7.27 (m, 5H), 4.44 (s, 2H), 4.09-3.99 (m, 2H), 3.66-3.60 (m, 1H), 3.42-3.35 (m, 2H), 2.71 (dd, 1H, J = 16.5 & 4.4 Hz), 2.45 (dd, 1H, J = 16.5 & 7.5 Hz), 2.44-2.41 (m, 1H), 2.16 (s, 1H), 1.61- 13 1.24 (m, 10H); C NMR (75 MHz, CDCl3): δ 208.0, 138.0, 128.3, 127.6, 127.5, 109.0, 76.3, 73.1, 70.5, 68.0, 42.2, 38.7, 36.1, 35.0, 32.7, 30.5, 25.1, 23.9; = -7.63 (c 1.17,

CHCl3); Anal. calcd. for C20H28O4 C, 72.26; H, 8.49. Found C, 72.45; H, 8.32.

Prop-1-en-2-ylbenzene (63) When Prop-1-en-2ylbenzene (63) was subjected to Wacker oxidation reaction, there was no any product formation. Starting material was recovered as it is.

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3.1.5 References 1. Phillips F.C., Z. Anorg. Chem., 1894, 6, 213-228. 2. Heck R.F., J.Am. Chem. Soc., 1968, 90, 5518; (b) Sivasanker, S. National Chemical Laboratory, Pune, India; Chemical Industry News (Mumbai, India) 2003, 48(10), 53-54. 3. (a) Miyaura, N., Suzuki A., Chem. Commun. 1979, 866; (b) Dembitsky, V. M., Abu Ali, H., Srebnik, M., Studies in Inorganic Chemistry, 2005, 22, 119-297. 4. (a) Sonogashira K., Tohda Y., Hagihara N., Tetrahedron Letters 1975, 16 (50), 4467–4470; (b) Campbell I. B., Glaxo Group Research, Ware, UK. Editor(s): Taylor, Richard J. K., Organocopper Reagents, 1994, 217-35. 5. (a) Frederic P., Joe Patt, John F. Hartwig, J. Am. Chem. Soc., 1994,116, 5969-5970; (b) Schlummer, B. Scholz, Ulrich. (Lanxess Deutschland G.m.b.H., Germany), Ger.Offen., 2006, 8 pp. 6. (a) Yoshihiko Ito, Toshikazu Hirao, and Takeo Saegusa, J. Org. Chem.; 1978, 43(5), 1011-1013; (b) Blake A. J., Highton A. J., Majid T. N., Simpkins N. S., OrganicvLetters, 1999, 1(11), 1787-1789. 7. (a) Mizoroki, T., Mori, K., Ozaki, A., Bull. Chem. Soc. Jap. 1971, 44, 581; (b) Miyaura, N., Tetrahedron Lett. 1979, 3437; (b) Miyaura N., Suzuki A., Chem. Commun., 1979, 866. 8. (a) Miyaura N., Suzuki A., Chem. Rev., 1995, 95, 2457-2483; (b) Rafael C. and Carmen N., Chem. Rev., 2007, 107(3), 874 -922. 9. (a) Karpov A. S., Müller T. J. J., Synthesis, 2003, 2815-2826; (b) Lemay A. B., Vulic K. S., Ogilvie W. W., J. Org. Chem., 2006, 71, 3615-3618;(c) Elangovan A., Wang Y. H., Ho T.I., Org. Lett., 2003, 5, 1841-1844. (d) Liang B., Dai M., Chen J., Yang Z., J. Org. Chem., 2005, 70, 391-393;(e) Kingston J. V., Verkade J. G., J. Org. Chem., 2007, 72, 2816-2822; (f) Mo J., Xiao J., Angew. Chem. Int. Ed., 2006, 45, 4152-4157. 10. (a) Heck R. F., Nolley Jr., J. P. J., Org. Chem. 1972, 37(14), 2320–232 (b) Sonogashira K., Tohda Y., Hagihara N., Tetrahedron Letters 1975, 16 (50); (c) Sonogashira K., Tohda Y., Hagihara N., Tetrahedron Letters,1975, 16 (50); (d) Li P., Wang L., Li H., Tetrahedron, 2005, 61, 8633-8640. (e) Mitsuru K., Daisuke K., and Koichi N.; ARKIVOC 2006, 3, 148-162; (f) Andrew G. M. and Peter S. D., Org. Synth., 1998, 9, 117 11. (a) Smidt, J. Chem. Ind., 1962, 54-62. (b) Tsuji J., Synthesis 1984, 5, 369-384. (c) Takacs J. M.; Jiang, X.T. Curr.; Org. Chem., 2003, 7, 369-396.

233

12. (a) Stahl S. S. Angew. Chem., Int. Ed., 2004, 33, 3400-3420. (b) Mueller, J. A., Goller, C. P., Sigman M. S. J. Am. Chem. Soc., 2004, 126, 9724-9734. 13. Tsuji J., Synthesis , 1984, 369–384 14. Sharma G.V.M. and Krishna P.R., Curr. Org. Chem., 2004, 8, 1187–1209 15. (a) Zweni P.P., and Alper H., Adv. Synth. Catal., 2004, 346, 849; (b) Choi K. M., Mizugaki T., Ebitani K., and Kaneda K., Chem. Lett., 2003, 32, 180; (c) Yokota T., Sakakura A., Tani M., Sakaguchi S. and Ishii Y., Tetrahedron Lett., 2002, 43, 8887; (d) Yokota T., Fujibayashi S., Nishiyama Y., Sakaguchi S. and Ishii Y., J. Mol.Catal. A.1996, 114, 113; (e) Tang H.G., and Sherrington D.C., J. Catal., 1993, 142, 540. 16. Ansari I.A., Joyasawal S., Gupta M.K., Yadav J.S. and Gree R., Tetrahedron Lett., 2005,46, 7507. 17. New Jersey Department of Health and Senior Services, Hazardous Substance Fact Sheet, Common Name: COPPER CHLORIDE, CAS Number: 7447-39-4, DOT Number: UN 2802, DOT Hazard Class: 8 (Corrosive), RTK Substance number: 0532, Date: February 1999 Revision: February 2007 18. (a)Tsuji J., Organic Synthesis, 1975, 113; (b) Zaw,K., Enary P. M., J. Org. Chem., 1990, 55, 1842. 19. Tsuji, J., Organic Synthesis, 1991, 7, 449. 20. Michel R. and Hubert M.; J. Org. Chem., 1980, 45, 5387-5390 21. Bodo B., Frederic L. and Paul K.; Tetrahedron Letters, 1998, 39, 6667-6670 22. Timothy T., Chem. Commun., 1993, 862. 23. Eric M., Sébastien T., Georges F., Yolande B., André M., Tetrahedron Letters, 1995, 36, 387-388 24. Mereyala H. B., Lingannagaru S. R., Tetrahedron, 1997, 53, 17501-17512 25. Amos B. S., Young S. C., and Gregory K. F., Tetrahedron Letters, 1998, 39, 8765- 8768 26. Arata K., Takashi H., Satoshi S., Yasutaka I., Tetrahedron Letters, 2000, 41, 99- 102 27. Marisa S. M., Alexandra L., Ulf S., Applied Catalysis A: General, 2004, 273, 217- 221 28. Ansari I.A., Joyasawal S., Gupta M. K., Yadav, J.S., Gree R., Tetrahedron Letters, 2005, 46, 7507-7510. 29. Takato M., Takuya U., Kohsuke M., Tomoo M., Kohki E., Kiyotomi K., Tetrahedron Letters, 2006, 47, 1425-1428.

234

30. Candace N. C. and Matthew S. S.; Org. Lett., 2006, Vol. 8, 4117-4120 31. Brian W. M., Jessica R. M., Andrea W., and Matthew S. S.; Angew. Chem., 2010, 49, 7312–7315 32. (a) Sheldon R. A., Acad C.R., Sci. Paris, Hc, Chim., Chem. 2000, 3, 541; (b) Sheldon, R. A. CHEMTECH 1994, 38. 33. (a) Smidt J.; Hafner W.; Jira R.; Sieber R.; Sedlmeier J.; Sabel A. Angew. Chem., 1962, 74, 93; (b) Clement W. H.; Selwitz C. M., J. Org. Chem., 1964, 29, 241; (c) Tsuji J. Synthesis, 1984, 369. 34. Auge, J. Green Chem., 2008, 10, 225. 35. (a) Clement W. H.; Selwitz C. M., J. Org. Chem., 1964, 29, 241; (b) Mimoun H.; Charpentier R.; Mitschler A.; Fischer J.; Weiss R., J. Am. Chem. Soc. 1980, 102,1047; (c) Roussel M.; Mimoun H., J. Org. Chem., 1980, 45, 5387; (d) Harada A.; Hu Y.; Takahashi S., Chem. Lett., 1986, 15, 2083; (e) Zahalka H. A.; Januszkiewicz K.; Alpe H., J. Mol. Catal. A: Chem., 1986, 35, 249; (f) Tsuji J.; Minato M., Tetrahedron Lett., 1987, 28, 3683; (g) Backvall J.E.; Hopkins R. B., Tetrahedron Letter, 1988, 29, 2885; (h) Nokami J.; Ogawa H.; Miyamoto S.; Mandai, T.; Wakabayashi S.; Tsuji J., Tetrahedron Letter 1988, 29, 5181; (i) Backvall J. E.; Hopkins R. B.; Grennberg H.; Mader M. M.; Awasthi A. K., J. Am.Chem. Soc.,1990, 112, 5160; (j) Miller D. G.; Wayner D. D. M., J. Org. Chem. 1990, 55, 2924; (k) Monflier E.; Blouet E.; Barbaux Y.; Mortreux A. Angew., Chem., Int. Ed. Engl.1994, 33, 2100; (l) Ahn J. H.; Sherrington D. C., Macromolecules, 1996, 29, 4164; (m) Stobbe-Kreemers A. W.; vander Zon M.; Makkee M.; Scholten, J. J. F., J. Mol.Catal. A: Chem., 1996, 107, 247; (n) Ten Brink G. J.; Arends, I. W. C. E.; Papadogianakis G.; Sheldon R. A., Chem. Commun. 1998, 2359; (o) Betzemeier B.; Lhermitte F.; Knochel P., Tetrahedron Lett., 1998, 39, 6667; (p) ten Brink G. J.; Arends I. W. C. E.; Papadogianakis G.; Sheldon R. A., Appl. Catal., A, 2000, 194–195, 435–442; (q) Karakhanov E.; Maximov A.; Kirillov A., J. Mol. Catal. A: Chem., 2000, 157, 25–30; (r) Nishimura T.; Kakiuchi N.; Onoue, T.; Ohe K.; Uemura S. J.,Chem. Soc., Perkin Trans., 2000, 1, 1915; (s) Karakhanov, E.; Buchneva, T.; Maximov, A.; Zavertyaeva, M., J. Mol. Catal. A: Chem. 2002, 184, 11–17; (t) Yokota, T.; Sakakura, A.; Tani, M.; Sakaguchi, S.; Ishii, Y., Tetrahedron Lett. 2002, 43, 8887; (u) Choi, K.-M.; Mizugaki, T.; Ebitani, K.; Kaneda, K., Chem. Lett., 2003, 32, 180;(v) Maksimov, A. L.; Buchneva, T. S.; Karakhanov, E. A., J. Mol. Catal. A: Chem. 2004, 217, 59– 67; (w) Cornell, C. N.; Sigman, M. S., J. Am. Chem. Soc. 2005, 127, 2796; (x)

235

Mitsudome, T.; Umetani, T.; Mori, K.; Mizugaki, T.; Ebitani, K.; Kaneda, K., Tetrahedron Lett. 2006, 47, 1425; (y) Mitsudome, T.; Umetani, T.; Nosaka, N.; Mori, K.; Mizugaki, T.; Ebitani, K.; Kaneda, K., Angew. Chem., Int. Ed. 2006, 45, 481; (z) Potekhinand, V. V.; Matsura, V. A., Russ. Chem. Bull., Int. Ed. 2006, 55, 650; (aa) Wang, J.-Q.; Cai, F.; Wang, E.; He, L.-N., Green Chem. 2007, 9, 882; (ab) Karakhanov, E. A.; Maksimov, A. L.; Runova, E. A.; Kardasheva, Y. S.; Terenina, M. V.; Kardashev, S. V.; Skorkin, V. A.; Karapetyan, L. M.; Talanova, M. Y. Russ., Chem. Bull., Int. Ed. 2008, 57, 780; (ac) Miller, A. L., II; Bowden, N. B., J. Org. Chem. 2009, 74, 4834; (ad) Ettedgui, J.; Neumann, R., J. Am. Chem. Soc. 2009, 131, 4; (ae) Karakhanov, E. A.; Maximov, A. L.; Tarasevich, B. N.; Skorkin, V. A., J. Mol.Catal. A:Chem. 2009, 297, 73; (af) Wang, J.-L.; He, L.-N.; Miao, C.-X.; Li, Y.-N., Green Chem.2009, 11, 1317; (ag) Michel, B. W.; Camelio, A. M.; Cornell, C. N.; Sigman, M. S., J.Am. Chem. Soc. 2009, 131, 6076; (ah) Mitsudome, T.; Mizumoto, K.; Mizugaki, T.; Jitsukawa, K.; Kaneda, K., Angew. Chem., Int. Ed. 2010, 49, 1238; (ai) Cornell, C. N.;Sigman, M. S., Org. Lett., 2006, 8, 4117; (aj) Naik, A.; Meina, L.; Zabel, M.; Reiser, O.Chem. Eur. J. 2010, 16, 1624; (ak) Michel, B. W.; McCombs, J. R.; Winkler, A.;Sigman, M. S., Angew. Chem., Int. Ed. 2010, 49, 7312. 36. Kulkarni M. G.; Bagale S. M.; Shinde M. P.; Gaikwad D. D.; Borhade A. S.; Dhondge A. P.; Chavhan S. W.; Shaikh Y. B.; Ningdale V. B.; Desai, M. P.; Birhade D. R., Tetrahedron Lett. 2009, 50, 2893. 37. (a) Rydberg, D. B.; Meinwald, J. Tetrahedron Lett. 1996, 37, 1129; (b) Srivastava, S.; Tripathi, H.; Singh, K., Transition Met. Chem. 2001, 26, 727; (c) Desai, S. M.; Halligudi, N. N.; Nandibewoor, S. T, Transition Met. Chem. 2002, 27, 207; (d) Mirjalili, B. F.; Zolfigol, M. A.; Bamoniri, A.; Zaghaghi, Z.; Hazar, A., Acta Chim. Slov.2003, 50, 563; (e) Shirini, F.; Zolfigoland, M. A.; Khaleghi, M. Phosphorus, Sulfur Silicon Relat. Elem. 2003, 178, 2107; (f) Bhat, S.; Ramesh, A. R.; Chandrasekaran, S., Synlett 1995, 329; (g) Adinolfi, M.; Barone, G.; Guariniello, L.; Iadonisi, A.,Tetrahedron Lett. 1999, 40, 8439; (h) Senthilkumar, P. M.; Aravind, A.; Baskaran, S., Tetrahedron Lett. 2007, 48, 1175; (i) Dess, D. B.; Martin, J. C., J. Am. Chem. Soc.1991, 113, 7277; (j) Zeynizadeh, B.; Dilmaghani, K. A.; Roozijoy, A., Synth.Commun. 2005, 35, 557; (k) McNeill, E.; Bois, J. D., J. Am. Chem. Soc.; 2010, 132,10202. 38. (a) Muzart J., Tetrahedron 2007, 63, 7505; (b) Weiner B.; Baeza A.; Jerphagnon T.; Feringa B. L.; J. Am. Chem. Soc. 2009, 131, 9473.

236