Supporting Information · 2016. 2. 24. · S3 Na2SO4 and the solvent was removed under vacuum to give the crude residue, which was finally subjected to column chromatography (hexane/ethylacetate)

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Temperature-controlled Mukaiyama aldol reaction of cyclododecanone (CDD) with aromatic aldehydes promoted by TMSCl via (TMS)3Si-

intermediate generated in situ†

VenkatesanSathesha,b, Kulathu I. Sathiyanarayanana*

aChemistry Division, School of Advanced Sciences, VIT University, Vellore-632014, Tamilnadu, India Fax: +914162243092; E-mail: [email protected]

b School of Chemical Sciences, National Institute of Science Education and Research (NISER), Institute of Physics Campus, Bhubaneswar-751005, Orissa, India.

Supporting Information

1. General Information ………………………………………………………………………S2

2. General Procedure for enonesand Mukaiyamaaldol addition reactions……………S2-S3

3. Spectral details………………………………………………………………………….S3-S17

3. Mechanism proof for the formation 1b, 1bb and 3d………………………………...S17-S24

3. NMR Spectra........................................................................................…......................S25-S54

Electronic Supplementary Material (ESI) for New Journal of Chemistry.This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2016

mailto:[email protected]

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General InformationAll Chemicals were purchased from commercial sources and they were used without further purification unless otherwise specified. TLC -Thin layer chromatography was performed on pre-coated silica gel on alumina platesusing UV light to visualize the course of reaction.Purification of reaction mixture was carried out by chromatography on silica gel and isolated yields after column chromatography arereported. Melting points were using microprocessor digital melting point apparatus and are uncorrected. IR spectra were recorded in the range 4000-400cm-1 using KBr pellet technique. 1H NMR and 13C NMR spectra were recorded at room temperature on a 400 MHz using CDCl3 as the solvent with TMS as an internal standard.The following abbreviations were used to designate chemical shift multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, p= pentet,multiplet, br = broad.HRMS analysis was obtained from double focusing electron impact method.Reactions involving air- or moisture-sensitive compounds wereconducted in appropriate shielded two neck round-bottomed flasks with magneticstirring bars and placed in 4◦A molecular sieves. CH3CN and DCM were distilled successivelyfrom P2O5and k2CO3.

General procedure for aldol condensation and Mukaiyamaaldol addition reactions

Illustrative procedure for the preparation of the enone (3a-q)

4Å molecular sieves, 2 mL of CH3CN, 10 mmol of trimethylsilyl chloride (TMSCl) and 5 mmol of cyclododecanone (CDD) were placed in a dry two-necked RB flask with stopcock, equipped with mechanical stirrer. The mixture was stirred at room temperature for 18 hours. Aldehyde (5 mmol) was added to the preformed intermediate1b over a period of 1 minute and the stirring was continued at 38oC, until the aldehyde was consumed. This process was monitored by TLC. The 4Å molecular sieves were removed through the filtration. HCl solution (1N, 4mL) was added to the reaction mixture and stirred at 38 oC for 1-2 min. Saturated NaHCO3aq solution (4 mL) and water (4 mL) was added. DCM (10 mL X 2) was added, and the aqueous layer was extracted with DCM. Organic layer was dried over anhydrous Na2SO4 and the solvent was removed under vacuum to give the crude residue, which was then subjected to column chromatography (hexane/ethylacetate) to give expected product in moderate to good yield as indicated in table 2.

Illustrative procedure for the Mukaiyamaaldol reaction (5)

In a dry two-necked RB flask with stopcock, placed in a ice/NaCl, equipped with mechanical stirrer, 4Å molecular sieves, 2 mL of CH3CN, 10 mmol of trimethylsilyl chloride (TMSCl), 5 mmol of NaI and 5 mmol of cyclododecanone (CDD) were added. This mixture was stirred at -20oC for 8 hours. Aldehyde (5 mmol) was added to the preformed enolsilyl ether1c over the period of 1 minute and the stirring was continued at -20oC, until the aldehydes were consumed. This process was monitored by TLC. The 4Å molecular sieves were removed through filtration. HCl solution (1N, 4mL) was added to the reaction mixture and was stirred at -20oC for 1-2 min. Saturated NaHCO3aq solution (4 mL) and water (4 mL) were added. Next, DCM (10 mL X 2) was added and the aqueous layer was extracted with DCM. The organic layer was dried over anhydrous

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Na2SO4 and the solvent was removed under vacuum to give the crude residue, which was finally subjected to column chromatography (hexane/ethylacetate). This produced the expected product in moderate to good yield as indicated in table 3.

Synthesis of (Z)-1-(2-propylidene)cyclododecanone (3a)

The crude product was subjected to column chromatography on silica gel (9:1 hexane:EtOAc) to

afford enone product 3a (0.91 g, 83% Z/E = 99/1); Rf 0.9 (9:1 hexane:EtOAc); FT-IR (KBr) υ =

2928.4, 2824.6, 1659.4 (C=O), 1465.4, 689.9. 1H NMR (400 MHz, CDCl3): δ = 2.40-2.37 (p, J

= 8, 4.4, 4Hz, 4H, CH2ali); 1.66-1.60 (p, J = 16, 8, 4Hz, CH2ali & terminal CH3 were merged);

1.22-1.17 (m, 14H, CH2ali); 0.90-0.82 (m, 2H). 13C NMR (100 MHz, CDCl3): δ = 211.8, 106.5,

66.3, 39.3, 28.4, 23.7, 23.5, 23.2, 22.8, 21.5, 21.3. HRMS (EI) m/z: Calc. for C15H26O; 222.1984

[M]+; Found 222.1981.

Synthesis of (Z)-1-(2-n-butylidene)cyclododecanone (3b)


afford enone product 3b (1.03 g, 87% Z/E = 99/1); Rf 0.9 (9:1 hexane:EtOAc); FT-IR (KBr) υ =

2932.5, 2828.7, 1659.8 (C=O), 1463.2, 687.9. 1H NMR (400 MHz, CDCl3): δ = 2.39-2.36 (p, J =

8.4, 4.4, 4Hz, 4H, CH2ali); 1.65-1.57 (p, J = 16, 8, 4Hz, 5H, CH2ali & terminal CH3 protons were

merged); 1.42-1.15 (m, 15H, CH2ali); 0.90-0.81 (m, 3H, CH2ali). 13C NMR (100 MHz, CDCl3): δ =

211.1, 38.5, 22.9, 22.8, 22.4, 20.7, 20.5, 12.1. HRMS (EI) m/z: Calc. for C16H28O; 236.2140 [M]+;

Found 236.2135.

Synthesis of (Z)-1-(2-Isobutylidene)cyclododecanone (3c)


afford enone product 3c (0.83 g, 70% Z/E = 99/1); Rf 0.9 (9:1 hexane:EtOAc); FT-IR (KBr) υ =

2935.6, 2827.3, 1660.1 (C=O), 1462.7, 674.2. 1H NMR (400 MHz, CDCl3): δ = 2.39-2.35 (p, J =

8, 6, 4Hz, 4H, CH2ali &methine of butyl group were merged); 1.65-1.59 (p, J = 10, 8, 8Hz, 4H, CH2ali); 1.30-1.08

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(m, 14H, CH2ali); 1.04-0.95 (m, 1H, CH2ali); 0.92-0.75 (m, 6H, CH2ali). 13C NMR (100 MHz,

CDCl3): δ = 211.1, 38.5, 22.9, 22.8, 22.4, 20.7, 20.5, 17.08. HRMS (EI) m/z: Calc. for C16H28O;

236.2140 [M]+; Found 236.2137.

Synthesis of (E)-2-benzylidenecyclododecanone (3d)


afford enone product 3d (1.13g, 83% E/Z = 99/1); Rf 0.7 (9:1 hexane:EtOAc); FT-IR (KBr) υ =

3066.1, 2938.5, 2825.7, 1660.5 (C=O), 1462.1, 1H NMR (400 MHz, CDCl3): δ = 7.38-7.36 (t, J =

8Hz, 1H, CHAr); 7.30-7.29 (d, J = 4Hz, 2H, CHAr); 7.27-7.15 (m, 2H, CHAr); 2.76-2.73 (t, J =

12Hz, 1H CH2ali); 2.59-2.57 (t, J = 8Hz, 1H CH2ali); 2.38-2.35 (t, J = 12Hz, 1H, CH2ali); 1.69=1.60

(m, 3H, CH2ali); 1.36 (bs, 1H, CH2ali), 1.21-1.81 (m, 15H, CH2ali). 13C NMR (100 MHz, CDCl3): δ

= 213.1 (CDD C=O), 205.5 (C=O), 170.9 (aldehydic O-TMSCl ), 142.7, 138.4, 136.0, 133.5,

130.1, 129.6, 129.0, 128.7, 128.6, 128.4, 128.1, 127.6, 127.5, 126.6, 40.3, 38.3, 26.6, 26.3, 25.1,

24.7, 24.6, 24.61, 24.46, 24.4, 24.3, 24.2, 23.5, 22.5, 22.3. HRMS (EI) m/z: Calc. for C20H28O;

284.2140 [M]+; Found 284.2143.

Synthesis of (E)-1-(2-methylbenzylidene)cyclododecanone (3e)


afford enone product 3e (1.24 g, 87% E/Z = 99/1); Rf 0.5 (9:1 hexane:EtOAc); mp-97-99oC; FT-

IR (KBr) υ =3053.5, 2942.3, 2855.7, 1662.6 (C=O), 1435.9, 1254.4, 1372.4, 1123.5, 827.2, 713.5.

1H NMR (400 MHz, CDCl3): δ = 7.45 (s, 1H, CHvinylic); 7.22-7.21 (m, 2H, CHAr); 7.21-7.18 (m,

2H, CHAr); 2.86-2.88 (m, 2H, CH2ali); 2.51-2.48 (t, 12Hz, 2H, CH2ali); 2.29 (s, 3H, CH3), 1.85-1.78

(m, 2H CH2ali); 1.38-1.25 (m, 12H, CH2ali); 1.14-1.12 (m, 2H, CH2ali). 13C NMR (100 MHz,

CDCl3): δ = 205.3 (C=O), 142.8 (C=C ali-ring), 137.9, 136.1, 135.4, 129.9, 128.6, 127.9, 125.5,

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38.5, 26.6, 26.4, 25.5, 24.4, 24.3, 24.1, 23.3, 22.5, 20.0. HRMS (EI) m/z: Calc. for C20H28O;

284.2140 [M]+; Found 284.2143.

Synthesis of (E)-1-((2-methoxynaphthalen-1-yl)methylene)cyclododecanone (3f)

The crude product was subjected to column chromatography on silica gel (4:1hexane:EtOAc) to

afford enone product 3f (1.14 g, 65% E/Z = 99/1); Rf 0.5 (4:1 hexane:EtOAc); mp-118-120oC; FT-

IR (KBr) υ = 3046.3, 2937.5, 2853.4, 1660.8, 1490.3, 239.4, 1025.3, 761.3. 1H NMR (400 MHz,

CDCl3): δ = 7.89-7.87 (d, J = 8Hz, 1H, CHAr); 7.84-7.82 (d, J = 8Hz, 1H, CHAr); 7.63 (s, 1H,

CHvinylic); 7.65-7.65 (d, J = 8Hz, 1H, CHAr); 7.49-7.45 (td, J = 14, 6, 4Hz, 1H, CHAr); 7.39-7.35

(m, 1H, CHAr); 7.34-7.31 (d, J = 12Hz, 1H, CHAr); 3.98 (s, 3H, OCH3); 2.97 (bs, 2H, CH2ali); 2.24

(bs, 2H, CH2ali) 2.01 (bs, 2H, CH2ali); 1.39 (bs, 6H, CH2ali); 1.26-1.14 (m, 6H, CH2ali); 0.98 (bs,

2H, CH2ali). 13C NMR (100 MHz, CDCl3): δ = 205.3 (C=O), 154.0, 144.4, 134.9, 131.5, 129.7,

128.7, 128.2, 126.7, 124.5, 123.6, 118.9, 112.4, 55.9 (C-OCH3), 39.2, (α′-CH2), 27.1, 26.7, 26.5,

24.7, 24.4, 23.9, 23.2, 22.7, 22.72. HRMS (EI) m/z: Calc. for C24H30O2; 350.2246 [M]+; Found

350.2247.

Synthesis of (E)-1-(2-chlorobenzylidene)cyclododecanone (3g)

The crude product was subjected to column chromatography on silica gel (n-hexane/EtOAc, 7/3)

to afford the enone product 3g (1.17 g, 77% E/Z = 99/1), Rf 0.5 (n-hexane/EtOAc, 4/1); mp: 93–

95oC ref. 25; FT-IR (KBr) υ = 3066.8, 2939.9, 2855.7, 1661.7 (C=O), 1465.4, 870.3, 767.8, 692.5.

1H NMR (400 MHz, CDCl3): δ = 7.45 (s, 1H, CHvinylic); 7.22-7.20 (t, J = 6, 1H, CHAr); 7.19-7.17

(m, 3H, CHAr); 2.86-2.83 (m, 2H, CH2ali); 2.51-2.44 (td, 24, 13.6, 6Hz, 2H, CH2ali); 2.29 (s, 2H,

CH2ali) 1.81-1.80 (d, J = 3.2Hz, 2H, CH2ali); 1.38-1.22 (m, 11H, CH2ali); 1.14-1.11 (m, 1H, CH2ali).

13C NMR (100 MHz, CDCl3): δ = 205.3 (C=O), 142.7, 138.0, 136.1, 135.4, 129.9, 128.6, 127.9,

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125.5, 38.5, 26.6, 26.4, 26.4, 25.5, 24.4, 24.3, 24.3, 24.1, 23.3, 22.5, 20.0. HRMS (EI) m/z: Calc.

for C19H25ClO; 304.1593 [M]+; Found 304.1594 [M]+1. Found 304.1590.

Synthesis of (E)-1-(2-bromobenylidene)cyclododecanone (3h)


to afford the enone product 3h (1.29 g, 74% E/Z = 98/2), Rf 0.6 (n-hexane/EtOAc, 4/1); mp: 111–

113oC ref. 25; FT-IR (KBr) υ = 3064.8, 2938.1, 2860.8, 1661.5 (C=O), 1464.8, 765.7, 742.3. 1H

NMR (400 MHz, CDCl3): δ = 7.56-7.54 (d, J = 8Hz, 1H, CHAr); 7.33 (bs, 1H, CHvinylic); 7.27-7.23

(t, J = 16Hz, 1H, CHAr); 7.19-7.17 (d, J = 8Hz, 1H, CHAr), 7.13-7.09 (t, J = 17.6Hz, 1H, CHAr),

2.80-2.77 (t, J = 13.6Hz, 2H, CH2ali); 2.46-2.43 (t, J = 11.2Hz, 2H, CH2ali); 1.81 (bs, 2H, CH2ali);

1.24-1.16 (m, 13H, CH2ali); 1.04 (bs, 2H, CH2ali). 13C NMR (100 MHz, CDCl3): δ = 205.6 (C=O),

142.8 (C=C ali-ring), 138.1, 136.6 (C=Cvinylic), 132.6, 130.5, 129.4, 127.1, 124.0, 38.8 (α′-CH2),

26.6, 26.5, 25.4, 24.4, 24.2, 24.1, 24.0, 23.1, 22.6. HRMS (EI) m/z: Calc. for C19H25BrO 348.1089

[M] +; Found 348.1086.

Synthesis of (E)-1-(3-hydroxybenylidene)cyclododecanone (3i)


to afford the enone product 3i (0.69 g, 67% E/Z = >99/1), Rf 0.5 (n-hexane/EtOAc, 4/1); mp: 132-

134; FT-IR (KBr) υ = 3333.5 (Ar-OH), 3069.7, 2935.9, 2863.5, 1666.2 (C=O), 1466.2, 687.4. 1H

NMR (400 MHz, CDCl3): δ = 7.41 (s, 1H, CHvinylic proton); 7.29-7.25 (m, 1H, CHAr); 6.96-6.94 (t, J

= 8Hz, 2H, CHAr); 6.89-6.87 (dd, J = 8, 2Hz, 1H, CHAr); 6.23 (bs, 1H, Ar-OH); 2.88-2.85 (p, J =

8,4, 4Hz, 2H, CH2ali); 2.71-2.68 (t, J = 12Hz, CH2ali); 1.79-1.78 (d, J = 3.2Hz, 2H, CH2ali); 1.45

(bs, 2H, CH2ali); 1.31-1.33 (m, 12H, CH2ali). 13C NMR (100 MHz, CDCl3): δ = 206.8 (C=O), 156.0

(Ar-OH), 142.7 (C=C ali-ring), 138.9, 137.3 (C=Cvinylic), 129.6, 121.4, 115.9, 115.4, 38.4 (α′-CH2),

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26.6, 26.3, 25.6, 24.6, 24.5, 24.4, 24.3, 23.4, 22.5. HRMS (EI) m/z: Calc. for C19H26O2 286.1933

[M] +; Found 286.1930.

Synthesis of (E)-1-(2,4-Dichlorobenylidene)cyclododecanone (3j)


to afford the enone product 3j (1.19 g, 70% E/Z = >99/1), Rf 0.6 (n-hexane/EtOAc, 4/1); mp: 140–

142oCref. 25; FT-IR (KBr) υ = 3072.0, 2930.2, 2856.3, 1667.9, 1581.9, 1466.2, 854.61, 755.08,

698.29. 1H NMR (400 MHz, CDCl3): δ = 7.464-7.459 (d, J = 2Hz, 1H, CHvinylic); 7.375 (s, 1H,

CHAr); 7.284-7.258 (dd, 8, 2Hz, 1H, CHAr); 7.231-7.210 (d, 8.4Hz, 1H, CHAr ); 2.862-2.831 (m,

2H, CH2ali); 2.517-2.831 (t, 12Hz, 2H, CH2ali);1.859-1.852 (s, 2H, CH2ali); 1.373-1.236 (m, 12H,

CH2ali); 1.117-1.091 (t, 10.4Hz, 2H, CH2ali). 13C NMR (100 MHz, CDCl3): δ = 204.7, 143.8, 134.4,

133.2, 131.1, 129.4, 126.9, 38.8, 26.5, 26.4, 25.5, 24.3, 24.2, 24.1, 24.0, 23.0, 22.5. HRMS (EI)

m/z: Calc. for C19H24Cl2O; 338.1204 [M] +; Found 338.1206.

Synthesis of (E)-2-(3-hydroxy-4-methoxybenzylidene)cyclododecanone (3k)


to afford the enone product 3k (0.92 g, 58% E/Z = 97/3), Rf 0.5 (n-hexane/EtOAc, 4/1); mp: 156–

156oC; FT-IR (KBr) υ =3334.6 (OH) 3067.3, 2932.8, 2868.9, 1661.5 (C=O), 1588.2, 1468.8,

767.5, 740.9. 1H NMR (400 MHz, CDCl3): δ = 7.37 (s, 1H, CHvinylic); 7.00-6.93 (m, 3H, CHAr);

5.95 (s, 1H, OH); 3.92 (s, 3H, OCH3); 2.85-2.81 (dd, J = 10, 8Hz, 2H, CH2ali); 2.75-2.71 (t, J =

15.6Hz, 2H, CH2ali ); 1.84 (bs, 2H, CH2ali); 1.77 (bs, 2H, CH2ali); 1.30-1.28 (t, J = 8Hz, 12H,

CH2ali). 13C NMR (100 MHz, CDCl3): δ = 205.4 (C=O), 146.3 (C-OCH3), 145.9 (C-OH), 141.1

(CH2-C=Cvinylic), 138.6 (C=Cvinylic), 128.1, 123.3, 114.5, 111.7, 56.0 (OCH3), 38.2 (α′-CH2), 26.6,

26.2, 25.5, 24.8, 24.5, 24.4, 24.3, 23.4, 22.7. HRMS (EI) m/z: Calc. for C20H28O3; 316.2038 [M]+;

Found 316.2038.

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Synthesis of (E)-1-(4-methoxybenzylidene)cyclododecanone (3l)


to afford the enone product 3l (1.05 g, 69% E/Z = 97/3), Rf 0.6 (n-hexane/EtOAc, 4/1); mp: 123-

125; FT-IR (KBr) υ = 3063.2, 2934.7, 2855.7, 1669.8 (C=O), 1578.5, 1025.42, 761.37, 667.8. 1H

NMR (400 MHz, CDCl3): δ = 7.322-7.302 (d, J = 8Hz, 3H, 2CHAr& 1CHvinylic protons are merged);

6.863-6.842 (d, J = 8Hz, 2H, CHAr); 3.768 (s, 3H, OCH3); 2.766-2.738 (t, J = 12Hz, 2H, α′- CH2ali);

2.644-2.616 (t, J = 12Hz, CH2ali); 1.694 (s, 2H, CH2ali); 1.404 (s, 2H, CH2ali); 1.192 (s, 12H,

6CH2ali). 13C NMR (100 MHz, CDCl3): δ = 205.3 (C=O), 159.6 (C-OCH3), 141.2, 138.2, 134.2,

130.1, 127.8, 113.9, 55.3 (OCH3), 38.2 (α′-CH2), 26.6, 26.2, 25.4, 24.7, 24.6, 24.47, 24.0, 23.5,

22.7. HRMS (EI) m/z: Calc. for C20H28O2 300.2089 [M] +; Found 300.2088.

Synthesis of (E)-1-(4-bromobenzylidene)cyclododecanone (3m)


to afford the enone product 3m (1.36 g, 78% E/Z= >99/1), Rf 0.6 (n-hexane/EtOAc, 4/1); mp: 108-

110oC; FT-IR (KBr) υ = 3064.8, 2938.1, 2860.8, 1661.5 (C=O), 1464.8, 765.7, 742.3. 1H NMR

(400 MHz, CDCl3): δ = 7.53-7.51 (d, J = 8Hz, 2H, CHAr); 7.33 (s, 1H, CHvinylic); 7.28-7.24 (t, J =

16Hz, 2H, CHAr); 2.85-2.82 (t, J = 12Hz, 2H, α′-CH2ali); 2.65-2.62 (t, J = 12Hz, 2H, CH2ali); 1.78

(bs, 2H, CH2ali); 1.48 (s, 2H, CH2ali); 1.45-1.27 (m, 13H, CH2ali). 13C NMR (100 MHz, CDCl3): δ

= 205.0 (C=O), 143.5, 136.8, 134.9, 132.4, 131.6, 131.4, 130.9, 130.8, 130.6, 122.2, 38.2, 26.5,

26.3, 26.3, 25.6, 24.77, 24.7, 24.6, 24.4, 24.33, 24.3, 24.2, 23.54, 23.5, 22.5, 22.3. HRMS (EI)

m/z: Calc. for C19H25BrO 348.1089 [M] +; Found 348.1088.

Synthesis of (E)-1-(4-cyanobenzylidene)cyclododecanone (3n)

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to afford the enone product 3n (0.87 g, 59% E/Z= >99/1), Rf 0.5 (n-hexane/EtOAc, 4/1); mp: 120-

122oC; FT-IR (KBr) υ = 3063.3, 2933.4, 2852.8, 1662.8 (C=O), 1587.8, 1466.9, 874.2, 767.4. 1H

NMR (400 MHz, CDCl3): δ = 7.70-7.68 (d, J = 8.4Hz, 2H, CHAr); 7.48-7.46 (d, J = 8Hz, 2H,

CHAr); 7.36 (S, 1H, CHvinylic); 2.86-2.83 (q, J = 7.6, 5.6Hz, 2H, CH2ali); 2.62-2.59 (t, J = 11.6Hz,

2H, CH2ali); 1.79 (bs, 2H, CH2ali); 1.48-1.41 (m, 2H, CH2ali); 1.32-1.23 (m, 12H, CH2ali). 13C NMR

(100 MHz, CDCl3): δ = 204.7, 145.3, 140.8, 138.7, 138.5, 135.5, 132.9, 132.2, 129.9, 129.5, 118.6,

117.7, 111.5, 38.2, 26.5, 26.2, 25.8, 24.8, 24.33, 24.3, 24.1, 23.6, 22.4. HRMS (EI) m/z: Calc. for

C20H25NO; 295.1936 [M]+; Found 295.1938.

Synthesis of (E)-1-(4-chlorobenzylidene)cyclododecanone (3o)


to afford the enone product 3o (1.24 g, 81% E/Z= >99/1), Rf 0.6 (n-hexane/EtOAc, 4/1); mp: 100-

102oC; FT-IR (KBr) υ = 3066.2, 2939.7, 2855.1, 1661.3 (C=O), 1568.9, 1462.0, 871.5, 767.4,

695.6. 1H NMR (400 MHz, CDCl3): δ = 7.39-7.28 (5H, 4HCHAr& 1Hvinylic proton are merged); 2.86-2.83

(dd, J = 8, 2.4Hz, 2H, CH2ali); 2.64-2.63 (t, J = 12Hz, 2H, CH2ali); 1.79 (bs, 2H, CH2ali); 1.46 (bs,

2H, CH2ali); 1.32-1.28 (m, 13H, CH2ali). 13C NMR (100 MHz, CDCl3): δ = 205.0 (C=O), 143.4,

136.7, 134.5, 134.0, 130.9, 130.3, 129.4, 128.6, 40.4, 38.2, 26.5, 26.3, 25.5, 24.7, 24.73, 24.6, 24.4,

24.3, 24.2, 23.5, 22.5, 22.3. HRMS (EI) m/z: Calc. for C19H25ClO; 304.1594 [M]+; Found

304.1589.

Synthesis of (E)-1-(4-nitrobenzylidene)cyclododecanone (3p)


to afford the enone product 3q (1.16 g, 73% E/Z= >99/1), Rf 0.5 (n-hexane/EtOAc, 4/1); mp: 116-

118oC; FT-IR (KBr) υ = 3083.2, 2940.5, 2852.1, 1665.7 (C=O), 1582.4, 1436.7, 698.29. 1H NMR

S10

(400 MHz, CDCl3): δ = 8.27-8.25 (d, J = 8Hz, 2H, CHAr); 7.54-7.52 (d, J = 8Hz, 2H, CHAr); 7.41

(s, 1H, CHvinylic proton); 2.88-2.85 (q, J = 8Hz, 2H, CH2ali); 2.64-2.61 (t, J = 12Hz, 2H, CH2ali); 1.80

(bs, 1H, CH2ali); 1.75 (bs, 1H, CH2ali); 1.49-1.42 (m, 2H, CH2ali); 1.33-1.22 (m, 12H, CH2ali). 13C

NMR (100 MHz, CDCl3): δ = 204.6 (C=O), 147.1 (Ar-NO2), 145.7 (C=Ccyclododecanone ring), 142.8

(C=CAr-ring), 135.0, 130.5, 129.7, 124.3, 123.7, 38.2, 26.5, 26.2, 25.9, 24.8, 24.33, 24.3, 24.1, 23.6,

22.4. HRMS (EI) m/z: Calc. for C19H25NO3; 315.1834 [M]+; Found 315.1830.

Synthesis of (E)-1-(3,4,5-hydroxybenzylidene)cyclododecanone (3q)


to afford the enone product 3r (0.85 g, 53% E/Z= >99/1), Rf 0.4 (n-hexane/EtOAc, 4/1); mp: 178-

180oC; FT-IR (KBr) υ = 3345.6 (OH) 3063.4, 2937.2, 2863.1, 1662.5 (C=O), 1586.7, 1464.8,

765.7, 742.3. 1H NMR (400 MHz, CDCl3): δ = 7.45 (s, 1H, CHvinylic proton); 7.29-7.24 (t, J = 20Hz,

2H, CHAr); 6.95-6.87 (m, 3H, Ar-OH); 2.86 (s, 2H, CH2ali); 2.69 (s, 2H, CH2ali); 1.78 (s, 2H,

CH2ali); 1.44-1.26 (m, 15H, CH2ali). 13C NMR (100 MHz, CDCl3): δ = 207.0 (C=O), 156.1 (Ar-

OH), 142.6 (C=Ccyclododecanone ring), 139.0 (C=CAr ring), 137.3, 129.6, 121.3, 115.9, 115.5, 38.4, 26.6,

26.3, 25.5, 24.6, 24.5, 24.4, 24.3, 23.4, 22.5. HRMS (EI) m/z: Calc. for C19H26O4; 318.1831 [M]+;

Found 318.1828.

Mukaiyamaaldol addition reaction

Synthesis of 2-(Hydroxy (phenyl) methyl) Cyclododecanone (5d)


afford Mukaiyamaaldol product 5d (1.17g, 81% dr= >99/1); Rf 0.48 (4:1 hexane:EtOAc); Mp:

107-109oC ref 25; FT-IR (KBr) υ = 3418.9 (OH), 3058.0, 2934.3, 2858.5, 1688.3(C=O), 1460.32,

1282.08, 951.33. 1H NMR (400 MHz, CDCl3): δ = 7.385-7.258 (m, 5H, CHAr); 4.823-4.783 (dd, J

= 8, 3.2Hz, 1H, CH*(OH)); 2.953-2.897 (td, J = 8.8, 4Hz, 1H, CH2ali); 2.804-2.728 (qd, J = 9.6,

S11

3.2Hz, 1H, CH2ali); 2.628-2.617 (d, J = 4.4Hz, 1H, CH2ali); 2.425-2.353 (qd, J = 8, 3.2Hz, 1H,

CH2ali); 1.892-1.825 (m, 1H, CH2ali); 1.606-1.571 (m, 1H, CH2ali); 1.531-1.473 (m, 1H, CH2ali);

1.392-1.160 (m, 15H, CH2ali). 13C NMR (100 MHz, CDCl3): δ = 214.9, 142.1, 128.5, 128.0, 126.6,


C19H28O2 288.2081 [M] +; Found 288.2089.

Synthesis of 2-(Hydroxy (2-tolyl) methyl) Cyclododecanone (5e)

The crude product was subjected to column chromatography on silica gel (4:1 n-

hexane/ethylacetate) to afford Mukaiyamaaldol product 5e (1.26g, 83%, dr= >99/1); Rf 0.68 (4:1

hexane:EtOAc); Mp: 127-129oC ref. 25; FT-IR (KBr) υ =3452.4 (OH), 3052.2, 2942.3, 2857.2,

1675.1 (C=O), 1041.2, 825.4, 715.3. 1H NMR (400 MHz, CDCl3): δ = 7.364.7.341 (d, J = 8.2Hz,

1H, CHAr); 7.213-7.154 (m, 3H, CHAr); 5.083-5.050 (dd, J = 9, 4.4Hz, 1H, CH*(OH)); 3.102-3.056

(td, J = 4.1, 2.4Hz, 1H, CH2ali); 2.740-2.668 (qd, J = 8.4, 3.6Hz, 1H, CH2ali); 2.604-2.593 (d, 4.4Hz,

1H, CH2ali); 2.589-2.459 (qd, J = 8.4, 3.2Hz, 1H, CH2ali); 2.398 (s, 3H, CAr-CH3); 1.832 (s, 1H,

OH); 1.780-1.619 (m, 2H, CH2ali); 1.315-1.135 (m, 15H, CH2ali). 13C NMR (100 MHz, CDCl3): δ

= 215.3, 140.2, 135.4, 130.6, 127.7, 126.4, 126.2, 71.7, 58.3, 39.9, 27.3, 26.3, 25.8, 24.3, 24.2,

24.1, 23.4, 22.4, 21.7, 19.4. HRMS (EI) m/z: Calc. for C20H30O2; 302.2245 [M] +; Found 302.2246.

Synthesis of 2-((2-bromophenyl) (hydroxy) methyl) Cyclododecanone (5h)


hexane/ethylacetate) to afford Mukaiyamaaldol product 5h (1.32g, 72%, dr= 98/2); Rf 0.7 (4:1

hexane:EtOAc); Mp: 136-138oC; FT-IR (KBr) υ = 3402.0 (OH), 3052.7, 2929.7, 2852.7, 1685.1

(C=O), 1589.9, 821.0, 730.4, 599.6. 1H NMR (400 MHz, CDCl3): δ = 7.57-7.55 (d, J = 8Hz, 1H,

CHAr); 7.45-7.43 (d, J = 8Hz, 1H, CHAr); 7.36-7.33 (m, 1H, CHAr); 7.18-7.15 (t, 14Hz, 1H, CHAr);

S12

5.24 (s, 1H, β-CHchiral), 3.22 (s, 2H, CH2ali), 2.56-2.50 (dd, J = 15.2, 8.8Hz, 1H, CH2ali); 2.33-2.27

(dd, J = 14, 4Hz, 1H, CH2ali), 1.87-1.86 (d, J = 4Hz, 1H, CH2ali) 1.72 (bs, 1H, β-OH); 1.64 (bs, 1H

CH2ali); 1.64-1.48 (bs, 1H, CH2ali); 1.32 (bs, 14H, CH2ali). 13C NMR (100 MHz, CDCl3): δ = 215.6

(C=O), 141.4, 132.9, 129.2, 128.0, 127.9, 122.6, 74.1 (β-CHchiral), 56.7 (α-CHchiral), 40.6 (α′-CH2),

28.0, 26.3, 25.6, 24.5, 24.4, 24.2, 23.8, 22.6, 21.7. HRMS (EI) m/z: Calc. for C19H27BrO2 366.1194

[M] +; Found 366.1189.

Synthesis of 2-((2,4-dichlorophenyl)(hydroxy)methyl)cyclododecanone (5j)


hexane/ethylacetate) to afford Mukaiyamaaldol and enone product 5j (1 g, 56%, dr= 98/2); Rf 0.8

(4:1 hexane:EtOAc); Mp: 156-158oC; FT-IR (KBr) υ = 3429.5(OH), 3072.0, 2930.2, 2856.3,

1682.3 (C=O of Mukaiyamaaldol product) 1667.9 (C=O of enone product), 1581.9, 1466.2,

1373.5, 1236.7, 1107.1, 854.6, 755.0, 698.2.1H NMR (400 MHz, CDCl3): δ = 7.48 (s, 0.21H,

CHvinylic proton); 7.42-7.39 (d, J = 12Hz, 2H, CHAr); 7.30-7.28 (d, J = 8Hz, 1H, CHAr); 5.32-5.25 (m,

1H, CHchiral); 3.28-3.26 (d, J = 8Hz, 1H, CH2ali); 3.14 (bs, 1H, CH2ali); 2.87-2.85 (t, J = 8Hz, 1H,

CH2ali); 2.63-2.57 (m, 1H, CH2ali); 2.53-2.50 (t, J = 10.8Hz, 1H, CH2ali); 2.33-2.27 (m, 1H, CH2ali);

1.86 (bs, 1H, CH2ali); 1.79 (bs, 1H, CH2ali); 1.66-1.60 (m, 1H, CH2ali); 1.50-1.49 (d, J = 4Hz, 1H,

CH2ali); 1.32-1.12 (m, 19H, CH2ali). 13C NMR (100 MHz, CDCl3): δ = 215.4 (C=O of Mukaiyamaaldol

product); 204.8 (C=O of enone product); 143.8, 138.6, 134.8, 134.6, 134.4, 133.9, 133.3, 133.0, 131.1,

129.4, 129.3, 128.9, 127.6, 126.9, 71.3, 56.6, 40.6, 38.8, 27.9, 26.5, 26.4, 26.3, 25.7, 25.5, 24.4,

24.3, 24.2, 24.1, 24.0, 23.9, 23.6, 23.0, 22.0, 22.6, 22.5, 21.6. HRMS (EI) m/z: Calc. for

C19H26Cl2O2; 356.1310 [M] +; Found 356.1308.

Synthesis of 2-(Hydroxy (2-methoxy phenyl) methyl) Cyclododecanone (5l)

S13


hexane/ethylacetate) to afford Mukaiyamaaldol and enone product 5l (1.37 g, 86%, dr= >99/1); Rf

0.7, (4:1 hexane:EtOAc); Mp: 147-149oC; FT-IR (KBr) υ = 3417.2 (OH), 3043.2, 2936.4, 2851.4,

1696.8 (C=O), 1490.2, 1025.42, 761.37. 1H NMR (400 MHz, CDCl3): δ = 7.27-7.25 (t, J = 8Hz,

2H, CHAr); 6.90-6.88 (d, J = 8Hz, 2H, CHAr); 4.80-4.77 (dd, J = 8, 4Hz, 1H CHchiral); 3.81 (s, 3H,

Ar-OCH3); 2.96-2.91 (td, 16, 8, 4,Hz, 1H, CH2ali); 2.81-2.73 (qd, J = 28, 16, 10, 4Hz, CH2ali); 2.38-

2.37 (d, J = 4Hz, 1H, CH2ali); 2.17 (s, 1H, CH2ali); 1.89-1.79 (dd, J = 12, 8Hz, 1H, CH2ali); 1.68-

1.61 (m, 3H, CH2ali& β-OH were merged); 1.53-1.45 (m, 1H, CH2ali); 1.31-1.18 (m, 14H, CH2ali).

13C NMR (100 MHz, CDCl3): δ = 215.0 (C=O), 159.4 (Ar-C-OCH3), 134.2, 117.8, 113.9, 74.8 (β-

CH-OH), 59.3 (α-CH*), 55.3 (OCH3), 39.2 (α′-CH2), 30.9, 27.3, 26.4, 26.0, 24.2, 23.8, 23.7, 22.7,

22.3, 21.6. HRMS (EI) m/z: Calc. for C20H30O3 318.2195 [M] +; Found 318.2189.

Synthesis of 2-((4-bromophenyl) (hydroxy) methyl) Cyclododecanone (5m)

The crude residue was then purified by column chromatography on silica gel (n-

hexane/ethylacetate 7:2) to afford Mukaiyamaaldol product 5m (1.47 g, 82%, dr= >99/1); Rf = 0.6,

Mp: 154-156oC ref. 25; FT-IR (KBr) υ = 3408.0, 3056.7, 2931.7, 2856.7, 1686.1 (C=O), 1589.9,

1043.02, 821.01, 730.46, 599.60. 1H NMR (400 MHz, CDCl3): δ = 7.49-7.46 (m, 2H, CHAr); 7.22-

7.20 (d, J = 8Hz, 2H, CHAr); 4.80-4.77 (dd, J = 8, 4Hz, 1H, CH*(OH)); 2.93-2.89 (td, J = 8, 4Hz,

1H, CH2ali); 2.80-2.74 (qd, J = 8, 4Hz, 2H, CH2ali); 2.43-2.36 (qd, J = 12, 4Hz, 1H, CH2ali ); 1.88-

1.81 (m, 1H, CH2ali); 1.63-1.45 (m, 2H, CH2ali); 1.37-1.20 (m, 15H, CH2ali). 13C NMR (100 MHz,

CDCl3): δ = 214.7, 141.1, 131.6, 128.3, 121.8, 74.5, 58.8, 39.7, 27.3, 26.3, 25.9, 24.2, 23.7, 23.7,

22.68, 22.3, 21.5. HRMS (EI) m/z: Calc. for C19H27BrO2; 366.1194 [M] +; Found 366.1194.

Synthesis of 2-((4-cyanophenyl) (hydroxy) methyl) Cyclododecanone (5n)

S14


hexane/ethylacetate 7:3) to afford Mukaiyamaaldol product 5n (g, 63%, dr= 85/15); Rf = 0.5, Mp:

188-190oC; FT-IR (KBr) υ = 3414.8, 3058.2, 2935.2, 2858.4, 1689.3 (C=O), 1592.9, 821.8, 733.8,

607.1. 1H NMR (400 MHz, CDCl3): δ = 7.69-7.61 (m, 2H, CHAr); 7.46-7.19 (m, 2H, CHAr); 4.31-

4.29 (d, J = 9.6Hz, 1H, CH*chiral proton); 3.26-3.21 (t, J = 20.4Hz, 1H, CH2ali); 1.77-1.14 (m, 5H,

CH2ali); 1.39-1.08 (m, 11H, CH2ali); 0.68-0.62 (m, 2H, CH2ali). 13C NMR (100 MHz, CDCl3): δ =

209.1(C=O), 145.9, 143.6, 134.2, 132.6, 132.5, 132.52, 132.2, 127.8, 127.1, 126.1, 118.4, 112.6,

112.2, 88.0, 82.0, 60.2, 56.5, 27.8, 26.9, 25.9, 24.4, 24.2, 23.4, 22.7, 22.5, 22.3, 21.8. HRMS (EI)

m/z: Calc. for C20H27NO2; 313.2042 [M] +; Found 313.2043.

Synthesis of 2-((4-chlorophenyl) (hydroxy) methyl) Cyclododecanone (5o)


hexane/ethylacetate 8:2) to afford Mukaiyamaaldol product 5o (1.29 g, 80%, dr= 88/2); Rf = 0.7,

Mp: 188-190oC ref. 25; FT-IR (KBr) υ = 3411.8, 3055.8, 2932.9, 2857.0, 1687.4 (C=O), 1596.6,

822.98, 731.68, 602.81. 1H NMR (400 MHz, CDCl3): δ = 7.343-7.338 (d, J = 2Hz, 1H, CHAr);

7.327-7.316 (t, J = 4.4Hz, 1H, CHAr); 7.286-7.280 (t, J = 2.4Hz, 1H, CHAr); 7.267-7.262 (d, J =

2Hz, 1H, CHAr); 4.835-4.802 (dd, J = 9.2, 4Hz, 1H, CH*(OH)); 2.954-2.896 (td, J = 8.8, 4Hz, 1H,

CH2ali); 2.814-2.738 (qd, J = 9.6, 3.2Hz, 1H, CH2ali); 2.628-2.617 (d, J = 4.4Hz, 1H, CH2ali); 2.425-

2.353 (qd, J = 8, 3.2Hz, 1H, CH2ali); 1.892-1.825 (m, 1H, CH2ali); 1.606-1.571 (m, 1H, CH2ali);

1.531-1.473 (m, 1H, CH2ali); 1.392-1.160 (m, 15H, CH2ali). 13C NMR (100 MHz, CDCl3): δ =

214.7, 140.6, 133.7, 128.7, 128.0, 74.4, 58.9, 39.7, 27.3, 26.4, 25.9, 24.2, 23.8, 23.7, 22.6, 22.4,

21.5. HRMS (EI) m/z: Calc. for C19H27ClO2; 322.1699 [M] +; Found 322.1700.

Synthesis of 2-((4-ethylphenyl) (hydroxy) methyl) Cyclododecanone (5r)

S15


hexane/ethylacetate 7:3) to afford Mukaiyamaaldol product 5s (1.25 g, 79%, dr= >99/1); Rf = 0.8;

Mp: 123-125oC ref. 25; FT-IR (KBr) υ = 3437.9 (OH), 3015.2, 2930.9, 2856.6, 1690.0 (C=O),

1509.8, 1465.6, 1038.8, 831.3, 732.1. 1H NMR (400 MHz, CDCl3): δ = 7.28-7.26 (d, J = 8Hz, 2H,

CHAr); 7.22-7.26 (d, J = 8Hz, 2H, CHAr); 4.82-4.80 (d, J = 9.2Hz, 1H, β-CHchiral); 3.00-2.95 (m,

1H, α-CHchiral); 2.81-2.75 (m, 1H, α′-CH2ali); 2.70-2.64 (q, J = 14.8, 7.6Hz, 2H, CH2ethyl); 2.53-

2.46 (m, 2H, CH2ali); 1.82-1.80 (t,J = 8Hz, 1H, α′-CH2ali); 1.70 (s, 1H, β-OH); 1.55-1.50 (q, J =

14.4, 6Hz, 1H, CH2ali); 1.33 (s, 3H, CH3ethyl which is merged with CH2ali protons) 1.281-1.22 (m, 15H, CH2ali).

13C NMR (100 MHz, CDCl3): δ = 214.9 (C=O), 144.1, 139.3, 128.0, 126.6, 75.2 (β-CH-OH), 59.3

(α-CH-CHOH), 39.2 (α′-CH2& ethyl CH2 are overlapped), 28.5, 27.3, 26.4, 24.2, 23.8, 23.7, 22.8,

22.3, 21.6, 15.5 (ethyl CH3) HRMS (EI) m/z: Calc. for C21H32O2 316.2402 [M] +; Found 316.2402.

Synthesis of 2-((3-fluoro-4-methoxyphenyl)(hydroxy)methyl)cyclododecanone (5s)

The crude product was subjected to column chromatography on silica gel (n-hexane/ethylacetate

7:3) to afford Mukaiyamaaldol product 5t (1 g, 59%, dr= >89/11); Rf = 0.8; Mp: 168-171oC; FT-

IR (KBr) υ = 3438.2 (OH), 3034.2, 2956.9, 2864.6, 1692.0 (C=O), 1502.4, 1466.1, 1037.4, 837.4,

734.3, 643.8. 1H NMR (400 MHz, CDCl3): δ = 7.16-7.11 (m, 1H, CHAr); 7.08-7.06 (d, J = 8Hz,

1H, CHAr); 6.99-6.95 (t, J = 16Hz, 1H, CHAr); 5.05-4.98 (dd, J = 20, 8Hz, 0.11H); 4.62-4.59 (d,

J = 12Hz, 0.89H, CH*chiral proton); 4.06-4.01 (dd, J = 16, 4Hz, 1H, CHali); 3.94 (s, 3H, CHAr-OCH3);

3.77-3.70 (dd, J = 16, 1.6Hz, 1H, CH2ali); 2.85-2.77 (m, 1H, CH2ali); 2.71-2.65 (m, 1H, CH2ali);

2.42 (s, 1H, β-OH), 2.06-1.19 (m, 1H, CH2ali); 1.75-1.63 (m, 1H, CH2ali); 1.33-1.27 (m, 12H,

CH2ali); 1.11-1.02 (m, 3H, CH2ali). 13C NMR (100 MHz, CDCl3): δ = 212.6(C=O), 153.7, 151.2,

147.8, 147.7, 131.3, 131.3, 124.1, 124.1, 115.3, 115.1, 113.1, 80.6, 79.0, 74.7, 59.4, 56.2, 55.0,

S16

39.0, 27.7, 26.7, 26.4, 26.1, 24.2, 23.7, 23.5, 23.0, 22.2, 21.6. HRMS (EI) m/z: Calc. for C20H29FO3;

336.2101 [M] +; Found 336.2099.

Synthesis of 2-(Hydroxy (4-tolyl) methyl) Cyclododecanone (5t)


8:2) to afford Mukaiyamaaldol product 5u (1.31 g, 87%, dr= >99/1); Rf = 0.7; Mp: 164-166oC ref.

25; FT-IR (KBr) υ = 3422.3 (OH), 3088.1, 2932.4, 2857.6, 1687.8 (C=O), 1463.4, 819.5, 730.5. 1H

NMR (400 MHz, CDCl3): δ = 7.25-7.23 (d, J = 8Hz, 2H, CHAr); 7.19-7.17 (d, J = 8Hz, 2H, CHAr);

4.80-4.78 (d, J = 8Hz, 1H, β-CH*Chiral proton); 2.99-2.93 (td, J = 20, 8, Hz, 1H, α-CH2ali); 2.81-2.73

(m, 1H, CH2ali); 2.55-2.44 (m, 2H, CH2ali); 2.37 (s, CHAr-CH3); 1.81-1.79 (t, J = 8Hz, 1H, CH2ali);

1.71 (bs, 1H, β-OH); 1.56-1.49 (m, 1H, CH2ali); 1.32-1.21 (m, 16H, CH2ali). 13C NMR (100 MHz,

CDCl3): δ = 215.0, 139.1, 137.7, 129.2, 126.6, 75.1, 59.3, 39.1, 27.3, 26.4, 26.0, 24.2, 23.8, 23.7,

22.8, 22.3, 21.6, 21.1. HRMS (EI) m/z: Calc. for C20H30O2; 302.2245 [M] +; Found 302.2246.

Synthesis of 2-(hydroxy (napthalen-1-yl) methyl) Cyclododecanone (5u)


7:3) to afford Mukaiyamaaldol product 4k (1.12 g, 66%, dr=>99/1); Rf = 0.7; Mp: 131-133oC ref.

25; FT-IR (KBr) υ = 3417.4 (OH), 3065.2, 2920.9, 2846.4, 1696.3 (C=O), 1517.5, 1453.6, 830.6,

736.1. 1H NMR (400 MHz, CDCl3): δ = 8.29-8.26 (d, J = 12Hz, 1H, CHAr); 7.92-7.90 (d, J =

6.4Hz, 1H, CHAr); 7.84-7.82 (d, J = 8Hz, 1H, CHAr); 7.59-7.47 (m, 4H, CHAr); 5.60-5.58 (d, J =

8Hz, 1H, CH*chiral proton); 3.45-3.40 (m, 1H, CH2ali); 2.95 (bs, 1H, OH); 2.74-2.68 (m, 1H, CH2ali);

2.46-2.68 (m, 1H, CH2ali); 1.82-1.64 (m, 3H, CH2ali); 1.32-1.12 (16H, CH2ali). 13C NMR (100 MHz,

CDCl3): δ = 215.5(C=O), 137.6, 134.0, 130.8, 129.0, 128.6, 126.2, 125.7, 125.3, 124.6, 123.5,


C23H30O2; 338.2245 [M] +; Found 338.2246.

S17

Mechanism proof for the formation of 1b, 1bb and the enone product formation of compound 3d

The reaction was carried out between CDD 1 (5 mmol) and TMSCl (10 mmol) in CDCl3 at 38oC for 18 hours stirring. The crude reaction mixture submitted to 1H, 13C NMR

a

b

c

d

e

f

Figure S1: The reaction was carried out in CDCl3 and the NMR recorded in CDCl3. (a) spectrum indicating cyclododecanone1 (b) spectrum indicating the stabilization of positive charge on the α-corner side of the CH2 group after the removal of silyl groups. (c) spectrum of in situ formation of TTMSS-CDD intermediate 1b (d) spectrum indicating the formation of TTMSS-CDD (1bb) from TTMSSH and this has stabilized the positive charge on the α-less hindered side of the CH2 group. (e) spectrum indicating the in situ formation of TTMSS-CDD from TMSCl after the addition of benzaldehyde and it can generate a siloxocarbenium ion intermediate 1d to 1e(f) formation of TTMSS-CDD from TTMSSH and after the addition of benzaldehyde it has not generated the siloxocarbenium ion aldol adducts.

1H NMR spectrum of TTMSSH

S18

13C NMR spectrum of TTMSSH

1H NMR spectrum of CDD 1ref .25

S19

13C NMR spectrum of CDD 1ref .25

After workup

OIn solution phase

O

1 1a

OIn solution phase

O

1 1a

S20

After the reaction mixture was diluted with hexane and the solvent was removed and the obtained white solid was submitted to 1H NMR and the results compare with original one (pure CDD).

1H NMR spectra: TMSCl stabilizes the positive charge on the α-corner side (C) of the CH2 group (figure S1B).

OTMSCl, CH3CN or CDCl34oA molecular sieves

38oC, stirring, 18h

OCl

1a 1b

CS

C = corner side, S = less hindered side

OO

R H

Si

2

SiOO

8-TTMSS

O In solution phase

1

SiTMS TMS

TMS

TMS

TMS

TMS

TMS

TMSTMS

Cl

R

1d1e

in situ generation of TTMSS from TMSCl

TTMSSH, CH3CN or CDCl34oA molecular sieves38oC, stirring, 18h

1bb

Si

TMS

2No, reaction either enone or

addition product

O

TMSTMS

Cl

R

OO SiTMS

TMS

TMSR

Cl

1H NMR forin situ formation of TTMSS-CDD from TMSCl and CDD (1b)

TMSCl, CH3CN, 4oA MS

38oC, stirring, 18h1a

O

stabilization of postive charge in corner side of CH2 groupC= corner side

C

S

S= less hindered side

OO

Cl

1b

SiTMS TMS

TMS



O


C

S


OO

Cl

1b

SiTMS TMS

TMS

S21

13C NMR for in situ formation of TTMSS-CDD from TMSCl and CDD (1b)



O


C

S


OO

Cl

1b

SiTMS TMS

TMS

S22

In situ formation of tris(trimethylsilyl)siloxy-cyclododecanone 1b (TTMSS-CDD) was confirmed by formation of tris(trimethylsilyl)siloxy-cyclododecanone 1bb (TTMSS-CDD) from commercial sources of tris(trimethylsilyl)silane (TTMSSH)

1H NMR for in situ formation of TTMSS-CDD from TTMSSH and CDD (1bb)

13C NMR for in situ formation of TTMSS-CDD from TTMSSH and CDD (1bb)



O

stabilization of postive charge in less hindere side of CH2 group

C= corner side

C

S


OOCl

1b

SiTMS

TMSTMS



O

stabilization of postive charge in less hindere side of CH2 group

C= corner side

C

S


OOCl

1b

SiTMS

TMSTMS

S23

1H NMR for in situ generation of (TMS)3Si-species in the absences of cyclododecanone

Parent benzaldehyde was added to the preformed 1b for the period of 1 minute the crude mixture was submitted to 1H, and 13C NMR.

1H NMR for the formation of enone3d

S24

13C NMR for the formation of enone3d

1H NMR spectrum: Preparation of silylenol ether from cyclododecanone (isolated 1c).

S25

1H NMR spectrum: silylenol ether from cyclododecanone 1c examined with parent benzaldehyde.

1H NMR spectrum for the formation of TTMSS-CDD from TTMSSH and after the addition of benzaldehyde it has not generated the siloxocarbenium ion aldol adducts.

S26

13C NMR spectrum for the formation of TTMSS-CDD from TTMSSH and after the addition of benzaldehyde it has not generated the siloxocarbenium ion aldol adducts.

1H NMR for (Z)-1-(2-propylidene)cyclododecanone (3a)

O

3a

S27

13C NMR for (Z)-1-(2-propylidene)cyclododecanone (3a)

1H NMR for (Z)-1-(2-n-butylidene)cyclododecanone (3b)

O

3b

O

3a

S28

13C NMR for (Z)-1-(2-n-butylidene)cyclododecanone (3b)

1H NMR for (Z)-1-(2-Isobutylidene)cyclododecanone (3c)

O

3c

O

3b

S29

13C NMR for (Z)-1-(2-Isobutylidene)cyclododecanone (3c)

1H NMR for (E)-2-benzylidenecyclododecanone (3d)

O

3d

O

3c

S30

13C NMR for (E)-2-benzylidenecyclododecanone (3d)

1H NMR for (E)-1-(2-methylbenylidene)cyclododecanone (3e)

O

3e

O

3d

S31

13C NMR for (E)-1-(2-methylbenylidene)cyclododecanone (3e)

1H NMR for (E)-1-((2-methoxynaphthalen-1-yl)methylene)cyclododecanone (3f)

O

3f

O

O

3e

S32

13C NMR for (E)-1-((2-methoxynaphthalen-1-yl)methylene)Cyclododecanone (3f)

1H NMR for (E)-1-(2-chlorobenylidene)cyclododecanone (3g)

3g

Cl

O

3f

O

S33

13C NMR for (E)-1-(2-chlorobenylidene)cyclododecanone (3g)

1H NMR for (E)-1-(2-bromobenylidene)cyclododecanone (3h)

O

3h

Br

3g

Cl

S34

13C NMR for (E)-1-(2-bromobenylidene)cyclododecanone (3h)

1H NMR for (E)-1-(3-hydroxybromobenylidene)cyclododecanone (3i)

O

3i

HO

O

3h

Br

S35

13C NMR for (E)-1-(3-hydroxybenylidene)cyclododecanone (3i)

1H NMR for (E)-1-(2,4-dicholorobenylidene)cyclododecanone (3j)

O

3j

Cl

Cl

O

3i

HO

S36

13C NMR for (E)-1-(2,4-dicholorobenylidene)cyclododecanone (3j)

1H NMR for (E)-2-(3-hydroxy-4-methoxybenzylidene)cyclododecanone (3k)

O

3k

HOOMe

O

3j

Cl

Cl

S37

13C NMR for (E)-2-(3-hydroxy-4-methoxybenzylidene)cyclododecanone (3k)

1H NMR for (E)-1-(4-methoxybenzylidene)cyclododecanone (3l)

O

3l

OMe

O

3k

HOOMe

S38

13C NMR for (E)-1-(4-methoxybenzylidene)cyclododecanone (3l)

1H NMR for (E)-1-(4-bromobenzylidene)cyclododecanone (3m)

O

3m

Br

O

3l

OMe

S39

13C NMR for (E)-1-(4-bromobenzylidene)cyclododecanone (3m)

1H NMR for (E)-1-(4-cyanobenzylidene)cyclododecanone (3n)

O

3n

NC

O

3m

Br

S40

13C NMR for (E)-1-((4-cyanobenzylidene)cyclododecanone (3n)

1H NMR for (E)-1-(4-chlorobenzylidene)cyclododecanone (3o)

O

3o

Cl

O

3n

NC

S41

13C NMR for (E)-1-(4-chlorobenzylidene)cyclododecanone (3o)

1H NMR for (E)-1-(4-nitrobenzylidene)cyclododecanone (3p)

O

3p

NO2

O

3o

Cl

S42

13C NMR for (E)-1-(4-nitrobenzylidene)cyclododecanone (3p)

1H NMR for (E)-1-(3,4,5-hydroxybenzylidene)cyclododecanone (3q)

O

3q

HO

HO OH

O

3p

NO2

S43

13C NMR for (E)-1-(3,4,5-hydroxybenzylidene)cyclododecanone (3q)

Mukaiyamaaldol reaction

Table 1, entry 18: mixture of anti/synMukaiyamaaldol product

OH

5d

O

O

3q

HO

HO OH

S44

1H NMR for 2-(Hydroxy (phenyl) methyl) Cyclododecanone (5d)

13C NMR for 2-(Hydroxy (phenyl) methyl) Cyclododecanone (5d)

OH

5d

O

OH

5d

O

S45

1H NMR for 2-(Hydroxy (2-tolyl) methyl) Cyclododecanone (5e)

13C NMR for2-(Hydroxy (2-tolyl) methyl) Cyclododecanone (5e)

OH

5e

O

OH

5e

O

S46

1H NMR for 2-((2-bromophenyl) (hydroxy) methyl) Cyclododecanone (5h)

13C NMR for 2-((2-bromophenyl) (hydroxy) methyl) Cyclododecanone (5h)

OOH

5h

Br

OOH

5h

Br

S47

1H NMR for 2-((2,4-dichlorophenyl)(hydroxy)methyl)cyclododecanone(5j)

13C NMR for 2-((2,4-dichlorophenyl)(hydroxy)methyl)cyclododecanone(11h)

OOH

5j

Cl

Cl

OOH

5j

Cl

Cl

S48

1H NMR for 2-(Hydroxy (2-methoxy phenyl) methyl) Cyclododecanone (5l)

13C NMR for2-(Hydroxy (2-methoxy phenyl) methyl) Cyclododecanone(11j)

OOH

5lO

OOH

5lO

S49

1HNMR for 2-((4-bromophenyl) (hydroxy) methyl) Cyclododecanone (5m)

13C NMR for 2-((4-bromophenyl) (hydroxy) methyl) Cyclododecanone (5m)

OH

Br5m

O

OH

Br5m

O

S50

1HNMR for 2-((4-cyanophenyl) (hydroxy) methyl) Cyclododecanone (5n)

13C NMR for 2-((4-cyanophenyl) (hydroxy) methyl) Cyclododecanone (5n)

OOH

5nCN

OOH

5nCN

S51

1HNMR for 2-((4-chlorophenyl) (hydroxy) methyl) Cyclododecanone (5o)

13C NMR for 2-((4-chlorophenyl) (hydroxy) methyl) Cyclododecanone (5o)

OOH

Cl5o

OOH

Cl5o

S52

1HNMR for 2-((4-ethylphenyl) (hydroxy) methyl) Cyclododecanone (5r)

13C NMR for 2-((4-ethylphenyl) (hydroxy) methyl) Cyclododecanone (5r)

OOH

5r

OOH

5r

S53

1HNMR for 2-((4-ethylphenyl) (hydroxy) methyl) Cyclododecanone (5s)

13C NMR for 2-((4-ethylphenyl) (hydroxy) methyl) Cyclododecanone (5t)

OOH

5sO

F

OOH

5sO

F

S54

1H NMR for 2-(Hydroxy (4-tolyl) methyl) Cyclododecanone (5t)

13C NMR for 2-(Hydroxy (4-tolyl) methyl) Cyclododecanone (5t)

OOH

5t

OOH

5t

S55

1H NMR for 2-(hydroxy (napthalen-1-yl) methyl) Cyclododecanone (5u)

13C NMR for 2-(hydroxy (napthalen-1-yl) methyl) Cyclododecanone (5u)

OOH

5u

OOH

5u

Documents

Supporting Information · 2016. 2. 24. · S3 Na2SO4 and the solvent was removed under vacuum to give the crude residue, which was finally subjected to column chromatography (hexane/ethylacetate)