Supporting Information · 2016. 2. 24. · S3 Na2SO4 and the solvent was removed under vacuum to...
Transcript of Supporting Information · 2016. 2. 24. · S3 Na2SO4 and the solvent was removed under vacuum to...
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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
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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)
The crude product was subjected to column chromatography on silica gel (9:1 hexane:EtOAc) to
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)
The crude product was subjected to column chromatography on silica gel (9:1 hexane:EtOAc) to
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)
The crude product was subjected to column chromatography on silica gel (9:1 hexane:EtOAc) to
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)
The crude product was subjected to column chromatography on silica gel (9:1 hexane:EtOAc) to
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)
The crude product was subjected to column chromatography on silica gel (n-hexane/EtOAc, 8/2)
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)
The crude product was subjected to column chromatography on silica gel (n-hexane/EtOAc, 7/3)
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)
The crude product was subjected to column chromatography on silica gel (n-hexane/EtOAc, 8/2)
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)
The crude product was subjected to column chromatography on silica gel (n-hexane/EtOAc, 7/3)
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)
The crude product was subjected to column chromatography on silica gel (n-hexane/EtOAc, 8/2)
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)
The crude product was subjected to column chromatography on silica gel (n-hexane/EtOAc, 8/2)
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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S9
The crude product was subjected to column chromatography on silica gel (n-hexane/EtOAc, 8/2)
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)
The crude product was subjected to column chromatography on silica gel (n-hexane/EtOAc, 8/2)
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)
The crude product was subjected to column chromatography on silica gel (n-hexane/EtOAc, 7/3)
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
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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)
The crude product was subjected to column chromatography on silica gel (n-hexane/EtOAc, 6/4)
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)
The crude product was subjected to column chromatography on silica gel (4:1 hexane:EtOAc) to
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,
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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,
75.3, 59.1, 39.5, 27.3, 26.3, 25.9, 24.2, 23.8, 23.8, 22.8, 22.3, 21.5. HRMS (EI) m/z: Calc. for
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)
The crude product was subjected to column chromatography on silica gel (4:1 n-
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);
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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)
The crude product was subjected to column chromatography on silica gel (4:1 n-
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)
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S13
The crude product was subjected to column chromatography on silica gel (4:1 n-
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)
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S14
The crude residue was then purified by column chromatography on silica gel (n-
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)
The crude residue was then purified by column chromatography on silica gel (n-
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)
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S15
The crude residue was then purified by column chromatography on silica gel (n-
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,
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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)
The crude product was subjected to column chromatography on silica gel (n-hexane/ethylacetate
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)
The crude product was subjected to column chromatography on silica gel (n-hexane/ethylacetate
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,
73.1, 57.7, 40.4, 28.2, 26.4, 25.8, 24.3, 24.33, 24.1, 23.4, 22.4, 21.9. HRMS (EI) m/z: Calc. for
C23H30O2; 338.2245 [M] +; Found 338.2246.
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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
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S18
13C NMR spectrum of TTMSSH
1H NMR spectrum of CDD 1ref .25
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S19
13C NMR spectrum of CDD 1ref .25
After workup
OIn solution phase
O
1 1a
OIn solution phase
O
1 1a
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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
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
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S21
13C NMR for in 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
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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)
TMSCl, CH3CN, 4oA MS
38oC, stirring, 18h1a
O
stabilization of postive charge in less hindere side of CH2 group
C= corner side
C
S
S= less hindered side
OOCl
1b
SiTMS
TMSTMS
TMSCl, CH3CN, 4oA MS
38oC, stirring, 18h1a
O
stabilization of postive charge in less hindere side of CH2 group
C= corner side
C
S
S= less hindered side
OOCl
1b
SiTMS
TMSTMS
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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
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S24
13C NMR for the formation of enone3d
1H NMR spectrum: Preparation of silylenol ether from cyclododecanone (isolated 1c).
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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.
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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
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S27
13C NMR for (Z)-1-(2-propylidene)cyclododecanone (3a)
1H NMR for (Z)-1-(2-n-butylidene)cyclododecanone (3b)
O
3b
O
3a
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S28
13C NMR for (Z)-1-(2-n-butylidene)cyclododecanone (3b)
1H NMR for (Z)-1-(2-Isobutylidene)cyclododecanone (3c)
O
3c
O
3b
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S29
13C NMR for (Z)-1-(2-Isobutylidene)cyclododecanone (3c)
1H NMR for (E)-2-benzylidenecyclododecanone (3d)
O
3d
O
3c
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S30
13C NMR for (E)-2-benzylidenecyclododecanone (3d)
1H NMR for (E)-1-(2-methylbenylidene)cyclododecanone (3e)
O
3e
O
3d
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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
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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
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S33
13C NMR for (E)-1-(2-chlorobenylidene)cyclododecanone (3g)
1H NMR for (E)-1-(2-bromobenylidene)cyclododecanone (3h)
O
3h
Br
3g
Cl
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
![Page 50: 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).](https://reader036.fdocuments.net/reader036/viewer/2022071420/6119b6b8bc161f6e0c3b86e7/html5/thumbnails/50.jpg)
S50
1HNMR for 2-((4-cyanophenyl) (hydroxy) methyl) Cyclododecanone (5n)
13C NMR for 2-((4-cyanophenyl) (hydroxy) methyl) Cyclododecanone (5n)
OOH
5nCN
OOH
5nCN
![Page 51: 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).](https://reader036.fdocuments.net/reader036/viewer/2022071420/6119b6b8bc161f6e0c3b86e7/html5/thumbnails/51.jpg)
S51
1HNMR for 2-((4-chlorophenyl) (hydroxy) methyl) Cyclododecanone (5o)
13C NMR for 2-((4-chlorophenyl) (hydroxy) methyl) Cyclododecanone (5o)
OOH
Cl5o
OOH
Cl5o
![Page 52: 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).](https://reader036.fdocuments.net/reader036/viewer/2022071420/6119b6b8bc161f6e0c3b86e7/html5/thumbnails/52.jpg)
S52
1HNMR for 2-((4-ethylphenyl) (hydroxy) methyl) Cyclododecanone (5r)
13C NMR for 2-((4-ethylphenyl) (hydroxy) methyl) Cyclododecanone (5r)
OOH
5r
OOH
5r
![Page 53: 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).](https://reader036.fdocuments.net/reader036/viewer/2022071420/6119b6b8bc161f6e0c3b86e7/html5/thumbnails/53.jpg)
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
![Page 54: 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).](https://reader036.fdocuments.net/reader036/viewer/2022071420/6119b6b8bc161f6e0c3b86e7/html5/thumbnails/54.jpg)
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
![Page 55: 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).](https://reader036.fdocuments.net/reader036/viewer/2022071420/6119b6b8bc161f6e0c3b86e7/html5/thumbnails/55.jpg)
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